N,N-disubstituted amic acid derivatives

ABSTRACT

The present invention relates to a compound of the formula (I): ##STR1## wherein Ar 1 , Ar 2 , Ar 3  and Ar 4  represent an aryl group or a heteroaromatic ring group; A represents a hydrocarbon group which may be substituted; X and Y represent an oxygen atom, a sulfur atom, a carbonyl group or a group of the formula --CHR a  -- (wherein R a  is a hydrogen atom or a lower alkyl group) or --NR b  -- (wherein R b  is a hydrogen atom or a lower alkyl group), or X and Y together represent a vinylene group or an ethynylene group; R 1 , R 2 , R 3 , R 8  and R 9  represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group; R 4  and R 5  represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl group, a lower hydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group, R 6  is a lower alkyl group, and R 7  is a hydrogen atom or a lower alkyl group, provided that when one of X and Y is an oxygen atom, a sulfur atom or a group of the formula --NR b  --, the other is a carbonyl group or a group of the formula --CHR a  --, its pharmaceutically acceptable salt or ester, and an antitumor agent containing it as an active ingredient.

This application is a division of application Ser. No. 08/616,464, filedMar. 15, 1996, now U.S. Pat. No. 5,849,747, which is acontinuation-in-part of PCT/J195/01589 filed Aug. 10, 1995.

TECHNICAL FIELD

The present invention relates novel N,N-disubstituted amic acidderivatives. More particularly, the N,N-disubstituted amic acidderivatives of the present invention inhibit protein-farnesyltransferase (PFT) in vivo thereby to suppress function of oncogeneprotein Ras and thus present antitumor activities, and they are thususeful as antitumor agents.

BACKGROUND ART

The ras oncogene is activated by mutation, and its translation productRas protein plays an important role in transformation of normal cells tocancer cells. Such activation of ras oncogene is observed in manycancers such as colorectal cancers or pancreatic cancers, and anproportion thereof is said to reach about 25% of the total humancancers. Accordingly, it is expected that canceration can be suppressedand antitumor effects can be obtained by suppressing such activation ofras oncogene, by inhibiting the function of Ras protein as its product.

Recently, it has been found that farnesyl-modification of Ras proteinitself is essential for function of Ras protein, and it is possible tosuppress localization of Ras protein at the plasma membrane byinhibiting this farnesyl-modification and thereby to inhibittransformation to cancer cells. The protein-farnesyl transferase (PFT)is an enzyme which catalyses this farnesyl-modification of Ras protein,and by inhibiting this enzyme, it is possible to suppress function ofcarcinogenic Ras protein. Further, this enzyme contributes tofarnesyl-modification of only very limited proteins in vivo.Accordingly, the inhibitor for such an enzyme is expected to be a safeand highly selective antitumor agent. From such a viewpoint, many PFTinhibitors have been developed in recent years (Cell, vol. 57, p.1167-1177 (1989); Proc. Natl. Acad. Sci., vol. 86, p. 8323-8327 (1989);ditto, vol. 90, p. 2281-2285 (1993); Science, vol. 245, p. 379-385(1989); ditto, vol. 260, p. 1934-1937 (1993); ditto, vol. 260, p.1937-1942 (1993); J. Biol. Chem., vol. 266, p. 15575-15578 (1991); J.Antibiotics, vol. 46, p. 222-227 (1993); Japanese Unexamined PatentPublications No. 201869/1993 and No. 213992/1993).

However, up to now, all of the reported PFT inhibitors have had someproblems for development as medicines, such that the activities are lowin cells, and the effects in vivo are inadequate.

DISCLOSURE OF INVENTION

It is an object of the present invention to provide a novel antitumoragent which inhibits the protein-farnesyl transferase (PFT) thereby toinhibit functional manifestation of oncogene protein Ras and which thusprovides antitumor effects.

The present inventors have found that a compound of the formula (I):##STR2## wherein each of ##STR3## which are the same or different, is anaryl group or a heteroaromatic ring group; A is a C₂₋₈ saturated orunsaturated aliphatic hydrocarbon group which may have substituent(s)selected from the group consisting of a lower alkyl group, a hydroxylgroup, a lower hydroxyalkyl group, a lower alkoxy group, a carboxylgroup, a lower carboxyalkyl group, an aryl group and an aralkyl group;each of X and Y which are the same or different, is an oxygen atom, asulfur atom, a carbonyl group or a group of the formula --CHR^(a) --(wherein R^(a) is a hydrogen atom or a lower alkyl group) or --NR^(b) '(wherein R^(b) is a hydrogen atom or a lower alkyl group), or X and Ytogether represent a vinylene group or an ethynylene group; each of R¹,R², R³, R⁸ and R⁹ which are the same or different, is a hydrogen atom, ahalogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxygroup; each of R⁴ and R⁵ which are the same or different, is a hydrogenatom, a halogen atom, a hydroxyl group, an amino group, a nitro group, acyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoylgroup, a lower alkylcarbamoyl group, a lower alkyl group, a lowerhydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group;R⁶ is a lower alkyl group; and R⁷ is a hydrogen atom or a lower alkylgroup, provided that when one of X and Y is an oxygen atom, a sulfuratom or a group of the formula --NR^(b) -- (wherein R^(b) is as definedabove), the other is a carbonyl group or a group of the formula--CHR^(a) -- (wherein R^(a) is as defined above), inhibits theprotein-farnesyl transferase (PFT) thereby to suppress function ofoncogene protein Ras, and thus is useful as an antitumor agent. Thepresent invention has been accomplished on the basis of this discovery.

Thus, the present invention relates to a compound of the formula (I) orits pharmaceutically acceptable salt or ester, as well as itsapplication as an antitumor agent.

Symbols and terms used in this specification will be explained.

The aryl group means a phenyl group, a naphthyl group or an anthrylgroup. A phenyl group or a naphthyl group is preferred.

The heteroaromatic ring group means a 5-membered or 6-memberedmonocyclic aromatic heterocyclic group containing one or twoheteroatoms, which are the same or different, selected from the groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom, or afused aromatic heterocyclic group having such a monocyclic aromaticheterocyclic group fused with the above-mentioned aryl group or havingthe same or different such monocyclic aromatic heterocyclic groups fusedwith each other, which may, for example, be a pyrrolyl group, animidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group,a pyrimidinyl group, a pyridazinyl group, an oxazolyl group, anisoxazolyl group, a furyl group, a thienyl group, a thiazolyl group, anisothiazolyl group, an indolyl group, a benzofuranyl group, abenzothienyl group, a benzimidazolyl group, a benzoxazolyl group, abenzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group,an indazolyl group, a purinyl group, a quinolyl group, an isoquinolylgroup, a phthalazinyl group, a naphthylidinyl group, a quinoxalinylgroup, a quinazolinyl group, a cinnolinyl group or a pteridinyl group.Among them, a furyl group, a thienyl group, a pyridyl group, apyrimidinyl group, an oxazolyl group, an isoxazolyl group, a thiazolylgroup, a benzofuranyl group, a benzothienyl group, a benzimidazolylgroup, a benzoxazolyl group, a benzothiazolyl group or a quinolyl groupis preferred.

The lower alkyl group means a C₁₋₆ linear or branched alkyl group, whichmay, for example, be a methyl group, an ethyl group, a propyl group, anisopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, apentyl group or a hexyl group. Among them, a methyl group or an ethylgroup is preferred.

The lower hydroxyalkyl group means the above-mentioned lower alkyl grouphaving a hydroxyl group, i.e. a C₁₋₆ hydroxyalkyl group, such as ahydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or ahydroxybutyl group. Among them, a hydroxymethyl group or a hydroxyethylgroup is preferred.

The lower alkoxy group means a C₁₋₆ alkoxy or alkylenedioxy group, whichmay, for example, be a methoxy group, an ethoxy group, a propoxy group,an isopropoxy group, a butoxy group, a tert-butoxy group, amethylenedioxy group, an ethylenedioxy group or a trimethylenedioxygroup. Among them, a methoxy group, an ethoxy group or a methylenedioxygroup is preferred.

The lower carboxyalkyl group means the above-mentioned lower alkyl grouphaving a carboxyl group, i.e. a C₁₋₇ carboxyalkyl group, such as acarboxymethyl group, a carboxyethyl group, a carboxypropyl group or acarboxybutyl group. Among them, a carboxymethyl group or a carboxyethylgroup is preferred.

The aralkyl group means the above-mentioned lower alkyl group having theabove-mentioned aryl group, such as a benzyl group, a phenethyl group, a3-phenylpropyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl groupor a 1-(2-naphthyl)ethyl group. Among them, a benzyl group, a phenethylgroup or a 2-naphthylmethyl group is preferred.

The saturated aliphatic hydrocarbon group may, for example, be anethylene group, a trimethylene group, a tetramethylene group, apentamethylene group, a hexamethylene group, a heptamethylene group oran octamethylene group. For example, a trimethylene group, atetramethylene group or a pentamethylene group is preferred.

The unsaturated aliphatic hydrocarbon group means an unsaturatedaliphatic hydrocarbon group having one or more, preferably one or twodouble bonds, at optional position(s) on the carbon chain, which may,for example, be a vinylene group, a propenylene group, a 1-butenylenegroup, a 2-butenylene group, a 1,3-butadienylene group, a 1-pentenylenegroup, a 2-pentenylene group, a 1,3-pentadienylene group, a1,4-pentadienylene group, a 1-hexenylene group, a 2-hexenylene group, a3-hexenylene group, a 1,3-hexadienylene group, a 1,4-hexadienylenegroup, a 1,5-hexadienylene group, a 1,3,5-hexatrienylene group, a1-heptenylene group, a 2-heptenylene group, a 3-heptenylene group, a1,3-heptadienylene group, a 1,4-heptadienylene group, a1,5-heptadienylene group, a 1,6-heptadienylene group, a1,3,5-heptatrienylene group, a 1-octenylene group, a 2-octenylene group,a 3-octenylene group, a 4-octenylene group, a 1,3-octadienylene group, a1,4-octadienylene group, a 1,5-octadienylene group, a 1,6-octadienylenegroup, a 1,7-octadienylene group, a 2,4-octadienylene group, a2,5-octadienylene group, a 2,6-octadienylene group, a 3,5-octadienylenegroup, a 1,3,5-octatrienylene group, a 2,4,6-octatrienylene group or a1,3,5,7-octatetraenylene group. Among them, a propenylene group, a1-butenylene group, a 1,3-butadienylene group or a 1-pentenylene groupis preferred.

The halogen atom may be a fluorine atom, a chlorine atom, a bromine atomor an iodine atom. For example, a fluorine atom or a chlorine atom ispreferred.

The lower alkoxycarbonyl group means a C₁₋₇ alkoxycarbonyl group, suchas a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonylgroup, a butoxycarbonyl group or a tert-butoxycarbonyl group. Amongthem, a methoxycarbonyl group or an ethoxycarbonyl group is preferred.

The lower alkylcarbamoyl group means a carbamoyl group mono-substitutedor di-substituted by the above-mentioned lower alkyl group, such as amethylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoylgroup or a diethylcarbamoyl group.

The lower fluoroalkyl group means the above-mentioned lower alkyl grouphaving fluorine atom(s), i.e. a C₁₋₆ fluoroalkyl group, such as afluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a1-fluoroethyl group, a 2-fluoroethyl group, a 2,2,2-trifluoroethyl groupor a pentafluoroethyl group.

The salt of the compound of the formula (I) may be a pharmaceuticallyacceptable common salt, which may, for example, be a base-addition saltof the terminal carboxyl group or of a carboxyl group when R⁴ and/or R⁵is a carboxyl group, or when a carboxyl group or a lower carboxyalkylgroup is present on a saturated or unsaturated aliphatic hydrocarbongroup represented by A in the formula (I), or an acid-addition salt ofan amino group when R⁴ and/or R⁵ is an amino group, or of a basicheteroaromatic ring when such a basic heteroaromatic ring is present.

The base-addition salt may, for example, be an alkali metal salt such asa sodium salt or a potassium salt; an alkaline earth metal salt such asa calcium salt or a magnesium salt; an ammonium salt; or an organicamine salt such as a trimethylamine salt, a triethylamine salt, adicyclohexylamine salt, an ethanolamine salt, a diethanolamine salt, atriethanolamine salt, a procaine salt or an N,N'-dibenzylethylenediaminesalt.

The acid-addition salt may, for example, be an inorganic acid salt suchas a hydrochloride, a sulfate, a nitrate, a phosphate or a perchlorate;an organic acid salt such as a maleate, a fumarate, a tartrate, acitrate, an ascorbate or a trifluoroacetate; or a sulfonic acid saltsuch as a methanesulfonate, an isethionate, a benzenesulfonate or ap-toluenesulfonate.

The ester of the compound of the formula (I) means a pharmaceuticallyacceptable common ester of the terminal carboxyl group or of a carboxylgroup when R⁴ and/or R⁵ is a carboxyl group, or when a carboxyl group ora lower carboxyalkyl group is present on the saturated or unsaturatedaliphatic hydrocarbon group represented by A in the formula (I). It may,for example, be an ester with a lower alkyl group such as a methylgroup, an ethyl group, a propyl group, an isopropyl group, a butylgroup, a sec-butyl group, a tert-butyl group, a cyclopropyl group or acyclopentyl group, an ester with an aralkyl group such as a benzyl groupor a phenethyl group, an ester with a lower alkenyl group such as anallyl group or a 2-butenyl group, an ester with a lower alkoxyalkylgroup such as a methoxymethyl group, a 2-methoxyethyl group or a2-ethoxyethyl group, an ester with a lower alkanoyloxyalkyl group suchas an acetoxymethyl group, a pivaloyloxymethyl group or a1-pivaloyloxyethyl group, an ester with a lower alkoxycarbonylalkylgroup such as a methoxycarbonylmethyl group or anisopropoxycarbonylmethyl group, an ester with a lower carboxyalkyl groupsuch as a carboxymethyl group, an ester with a loweralkoxycarbonyloxyalkyl group such as a 1-(ethoxycarbonyloxy)ethyl groupor a 1-(cyclohexyloxycarbonyloxy)ethyl group, an ester with a lowercarbamoyloxyalkyl group such as a carbamoyloxymethyl group, an esterwith a phthalidyl group, or an ester with a(5-substituted-2-oxo-1,3-dioxol-4-yl)methyl group such as a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group.

Further, when a hydroxyl group is present at the γ- or δ-position of theterminal carboxyl group or of a carboxyl group when such a carboxylgroup or a lower carboxyalkyl group is present on the saturated orunsaturated aliphatic hydrocarbon group represented by A in the formula(I), such a hydroxyl group and a carboxyl group may form anintramolecular ester i.e. a 5-membered or 6-membered lactone ring.

Further, the compound of the present invention may have stereoisomerssuch as optical isomers, diastereomers or geometrical isomers, dependingupon the form of its substituents. The compound of the present inventionincludes all of such stereoisomers and their mixtures. Among them, acompound of the formula (I-1): ##STR4## or the formula (I-2): ##STR5##wherein ##STR6## A, X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are asdefined above, is preferred.

Among compounds of the formula (I), a compound wherein ##STR7## is aphenyl group and a compound wherein ##STR8## is a naphthyl group, abenzofuranyl group or a benzothienyl group, are preferred.

Each of X and Y which are the same or different, is an oxygen atom, asulfur atom, a carbonyl group or a group of the formula --CHR^(a) --(wherein R^(a) is a hydrogen atom or a lower alkyl group) or --NR^(b) --(wherein R^(b) is a hydrogen atom or a lower alkyl group), or X and Ytogether represent a vinylene group or an ethynylene group. However,when one of X and Y is an oxygen atom, a sulfur atom or a group of theformula --NR^(b) -- (wherein R^(b) is as defined above), the other is acarbonyl group or a group of the formula --CHR^(a) -- (wherein R^(a) isis as defined above).

Referring to the formula (I), a compound wherein X is --NR^(b) --(wherein R^(b) is as defined above), and Y is a carbonyl group, acompound wherein X is an oxygen atom, and Y is --CHR^(a) -- (whereinR^(a) is as defined above), a compound wherein each of X and Y is agroup of the formula --CHR^(a) -- (wherein R^(a) is as defined above),or a compound wherein X and Y together represent a vinylene group, ispreferred.

The C₂₋₈ saturated or unsaturated aliphatic hydrocarbon group which mayhave substituent(s) selected from the group consisting of a lower alkylgroup, a hydroxyl group, a lower hydroxyalkyl group, a lower alkoxygroup, a carboxyl group, a lower carboxyalkyl group, an aryl group andan aralkyl group, for A in the compound of the formula (I), means theabove-mentioned saturated aliphatic hydrocarbon group or theabove-mentioned unsaturated aliphatic hydrocarbon group, which isunsubstituted or which may have substituent(s) at optional position(s)for substitution. Such substituent(s) may be one or more, preferablyfrom one to three members, which are the same or different, selectedfrom the group consisting of a lower alkyl group, a hydroxyl group, alower hydroxyalkyl group, a lower alkoxy group, a carboxyl group, alower carboxyalkyl group, an aryl group and an aralkyl group.

Preferred is a compound wherein A is a group of the formula (a):##STR9## wherein R¹⁰ is a hydrogen atom, a hydroxyl group, a lowerhydroxyalkyl group, a lower alkoxy group or a carboxyl group; R¹¹ is ahydrogen atom, a hydroxyl group, a lower alkoxy group, a carboxyl groupor a lower carboxyalkyl group; R¹² is a hydrogen atom, a lowerhydroxyalkyl group or a carboxyl group; R¹³ is a hydrogen atom, ahydroxyl group or a carboxyl group; and each of m and n which are thesame or different, is an integer of from 0 to 2, or a compound wherein Ais a group of the formula (b): ##STR10## wherein R¹² is a hydrogen atom,a lower hydroxyalkyl group or a carboxyl group; R¹³ is a hydrogen atom,a hydroxyl group or a carboxyl group; p is 0 or 1; and each of q and rwhich are the same or different, is an integer of from 0 to 2.

When A is a group of the formula (a), R¹⁰ is preferably a hydrogen atom,a hydroxyl group or a carboxyl group, R¹¹ is preferably a carboxyl groupor a lower carboxyalkyl group such as a carboxymethyl group, each of R¹²and R¹³ is preferably a hydrogen atom or a carboxyl group, and each of mand n which are the same or different, is preferably 0 or 1.

When A is a group of the formula (b), R¹² is preferably a lowerhydroxyalkyl group such as a hydroxymethyl group, or a carboxyl group,and R¹³ is preferably a hydrogen atom, and each of p, q and r ispreferably 0.

Further, it is well known that in the case of a compound having apartial structure of the formula (b), there exist enol form and ketoform tautomers, as shown below. The compound of the present inventionincludes such enol form and keto form isomers and their mixtures.##STR11## In the above formulas, R¹², R¹³, p, q and r are as definedabove.

Each of R¹ and R² which are the same or different, is a hydrogen atom, ahalogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxygroup, and may be substituted at an optional position for substitutionon the aryl group or the heteroaromatic ring group represented by theformula ##STR12##

R³ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylgroup or a lower alkoxy group, and may be substituted at an optionalposition for substitution on the aryl group or the heteroaromatic ringgroup represented by the formula ##STR13##

Further, in the formula (I), the group of the formula ##STR14## may alsobe substituted at an optional position for substitution on theabove-mentioned aryl or the heteroaromatic ring group in the same manneras R³.

Each of R⁴ and R⁵ which are the same or different, is a hydrogen atom, ahalogen atom, a hydroxyl group, an amino group, a nitro group, a cyanogroup, a carboxyl group, a lower alkoxycarbonyl group, a carbamoylgroup, a lower alkylcarbamoyl group, a lower alkyl group, a lowerhydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group.Each of them may be substituted at an optional position for substitutionon the aryl or heteroaromatic ring group represented by the formula##STR15##

R⁶ is preferably a methyl group, an ethyl group or a propyl group.Particularly preferred is a methyl group or an ethyl group.

R⁷ is preferably a hydrogen atom, a methyl group, an ethyl group or apropyl group. Particularly preferred is a hydrogen atom or a methylgroup.

Each of R⁸ and R⁹ which are the same or different, is a hydrogen atom, ahalogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxygroup, and each of them may be substituted at an optional position forsubstitution on the aryl or heteroaromatic ring group represented by theformula ##STR16##

Now, processes for producing the compound of the present invention willbe described.

The compound of the formula (I) of the present invention can beprepared, for example, by the following process 1, 2, 3, 4, 5 or 6.

Process 1

The compound of the formula (I) can be prepared by reacting a compoundof the formula (II): ##STR17## wherein each of ##STR18## which are thesame or different, is an aryl group or a heteroaromatic ring group; eachof X^(p) and Y^(p) which are the same or different, is an oxygen atom, asulfur atom, a carbonyl group or a group of the formula --CHR^(a) --(wherein R^(a) is a hydrogen atom or a lower alkyl group) or --NR^(bp)-- (wherein R^(bp) is a hydrogen atom, a lower alkyl group or animino-protecting group), or X^(p) and Y^(p) together represent avinylene group or an ethynylene group; each of R^(1p), R^(2p), R^(3p),R^(8p) and R^(9p) which are the same or different, is a hydrogen atom, ahalogen atom, a hydroxyl group which may be protected, a lower alkylgroup or a lower alkoxy group; each of R^(4p) and R^(5p) which are thesame or different, is a hydrogen atom, a halogen atom, a nitro group, acyano group, a lower alkoxycarbonyl group, a carbamoyl group, a loweralkylcarbamoyl group, a lower alkyl group, a lower fluoroalkyl group, alower alkoxy group or a hydroxyl, amino, carboxyl or lower hydroxyalkylgroup which may be protected; R⁶ is a lower alkyl group; and R⁷ is ahydrogen atom or a lower alkyl group, provided that when one of X^(p)and Y^(p) is an oxygen atom, a sulfur atom or a group of the formula--NR^(bp) -- (wherein R^(bp) is as defined above), the other is acarbonyl group or a group of the formula --CHR^(a) -- (wherein R^(a) isas defined above), with a carboxylic acid of the formula (III) or itsreactive derivative: ##STR19## wherein A^(p) is a C₂₋₈ saturated orunsaturated aliphatic hydrocarbon group which may have substituent(s)selected from the group consisting of a lower alkyl group, a loweralkoxy group, an aryl group, an aralkyl group, and hydroxyl, lowerhydroxyalkyl, carboxyl and lower carboxyalkyl groups which may beprotected; and R^(p) is a hydrogen atom or a carboxyl-protecting group,to obtain a compound of the formula (IV): ##STR20## wherein ##STR21##A^(p), X^(p), Y^(p), R^(1p), R^(2p), R^(3p), R^(4p), R^(5p), R⁶, R⁷,R^(8p), R^(9p) and R^(p) are as defined above, and, if necessary,removing any protecting group.

As the reactive derivative of the carboxylic acid of the formula (III),an acid halide, a mixed acid anhydride, an active ester or an activeamide may, for example, be used.

When the carboxylic acid of the formula (III) is used, it is preferredto conduct the reaction in the presence of a condensing agent such asN,N'-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or2-chloro-1,3-dimethylimidazolyl chloride.

The reaction of the compound of the formula (II) with the carboxylicacid of the formula (III) or its reactive derivative, is conductedusually by using 1 mol or an excess molar amount, preferably from 1 to 5mols, of the carboxylic acid of the formula (III) or its reactivederivative, per mol of the compound of the formula (II).

The reaction is conducted usually in an inert solvent. The inert solventmay, for example, be a halogenated hydrocarbon such as methylenechloride, chloroform, carbon tetrachloride, dichloroethane ortrichloroethylene; an ether such as ethyl ether, tetrahydrofuran ordioxane; an aromatic hydrocarbon such as benzene, toluene, chlorobenzeneor xylene; an aprotic polar solvent such as dimethylformamide,acetonitrile, acetone, ethyl acetate or hexamethylphosphoric triamide,or a mixture of such solvents.

The reaction temperature is usually from -70° C. to the boiling point ofthe solvent used for the reaction, preferably from -20° C. to 100° C.

The reaction time is usually from 5 minutes to 7 days, preferably from10 minutes to 24 hours.

The above reaction can be conducted in the presence of a base tofacilitate the reaction.

As such a base, it is preferred to conduct the reaction in the presenceof an inorganic base such as sodium hydroxide, potassium hydroxide,calcium hydroxide, sodium carbonate, potassium carbonate or sodiumhydrogencarbonate, or an organic base such as triethylamine,N-ethyldiisopropylamine, pyridine, 4-dimethylaminopyridine orN,N-dimethylaniline.

Such a base is used usually in an amount of 1 mol or an excess molaramount, preferably from 1 to 5 mols, per mol of the reactive derivativeof the carboxylic acid of the formula (III).

The acid halide of the compound of the formula (III) can be obtained byreacting the carboxylic acid of the formula (III) with a halogenatingagent in accordance with a conventional method. As the halogenatingagent, thionyl chloride, phosphorus trichloride, phosphoruspentachloride, phosphorus oxychloride, phosphorus tribromide, oxalylchloride or phosgene may, for example, be used.

The mixed acid anhydride of the compound of the formula (III) can beobtained by reacting the carboxylic acid of the formula (III) with analkyl chlorocarbonate such as ethyl chlorocarbonate or with an aliphaticcarboxylic acid chloride such as acetyl chloride, in accordance with aconventional method. Further, an intramolecular acid anhydride may beformed between carboxyl groups at both terminals, or when in the formula(III), a carboxyl group is present on the saturated or unsaturatedaliphatic hydrocarbon group for A^(p), an intramolecular acid anhydridemay be formed between such a carboxyl group and a carboxyl group to beinvolved in the reaction, to constitute a reactive derivative of thecarboxylic acid.

The active ester of the compound of the formula (III) can be prepared byreacting the carboxylic acid of the formula (III) with an N-hydroxycompound such as N-hydroxysuccinimide, N-hydroxyphthalimide or1-hydroxybenzotriazole, or a phenol compound such as a 4-nitrophenol,2,4-dinitrophenol, 2,4,5-trichlorophenol or pentachlorophenol, in thepresence of a condensing agent such as N,N'-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in accordance with aconventional method.

The active amide of the compound of the formula (III) can be prepared byreacting the carboxylic acid of the formula (III) with e.g.1,1'-carbonyldiimidazole or 1,1'-carbonylbis(2-methylimidazole) inaccordance with a conventional method.

When a hydroxyl group is present on the group of the formula ##STR22##when a hydroxyl group, a lower hydroxyalkyl group, a carboxyl group or alower carboxyalkyl group is present on the saturated or unsaturatedaliphatic hydrocarbon group represented by A^(p), and when a hydroxylgroup, an amino group, a carboxyl group or a lower hydroxyalkyl group ispresent on the group of the formula ##STR23##

it is preferred to conduct the reaction after protecting such a hydroxylgroup, a lower hydroxyalkyl group, an amino group, a carboxyl group or alower carboxyalkyl group appropriately by a hydroxyl-protecting group,an amino-protecting group or a carboxyl-protecting group and removingthe protecting group after the reaction. Further, in a case where one ofX^(p) and Y^(p) is a group of the formula --NR^(bp) -- (wherein R^(bp)is as defined above), and the other is a group of the formula --CHR^(a)-- (wherein R^(a) is as defined above), R^(bp) is preferably a loweralkyl group or an imino-protecting group, and when R^(bp) is animino-protecting group, it is preferred to remove such a protectinggroup after the reaction.

The hydroxyl-protecting group may, for example, be a lower alkylsilylgroup such as a trimethylsilyl group or a tert-butyldimethylsilyl group;a lower alkoxymethyl group such as a methoxymethyl group or a2-methoxyethoxymethyl group; a tetrahydropyranyl group; an aralkyl groupsuch as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl groupor a trityl group; or an acyl group such as a formyl group or an acetylgroup. Particularly preferred is a methoxymethyl group, atetrahydropyranyl group, a trityl group, a tert-butyldimethylsilyl groupor an acetyl group.

The amino- or imino-protecting group may, for example, be an aralkylgroup such as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzylgroup, a benzhydryl group or a trityl group; a lower alkanoyl group suchas a formyl group, an acetyl group, a propionyl group, a butyryl groupor a pivaloyl group; a lower haloalkanoyl group such as atrifluoroacetyl group; a lower alkoxycarbonyl group such as amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl groupor a tert-butoxycarbonyl group; a lower haloalkoxycarbonyl group such asa 2,2,2-trichloroethoxycarbonyl group; an alkenyloxycarbonyl group suchas a 2-propenyloxycarbonyl group; an aralkyloxycarbonyl group such as abenzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group; or a loweralkylsilyl group such as a trimethylsilyl group or atert-butyldimethylsilyl group. Further, the amino-protecting group may,for example, be an aralkylidene group such as a benzylidene group, ap-chlorobenzylidene group or a p-nitrobenzylidene group. Particularlypreferred is an acetyl group, a trifluoroacetyl group, atert-butoxycarbonyl group or a benzyloxycarbonyl group.

The carboxyl-protecting group may, for example, be a lower alkyl groupsuch as a methyl group, an ethyl group, a propyl group, an isopropylgroup or a tert-butyl group; a lower haloalkyl group such as a2,2,2-trichloroethyl group; a lower alkenyl group such as 2-propenylgroup; or an aralkyl group such as a benzyl group, a p-methoxybenzylgroup, a p-nitrobenzyl group, a benzhydryl group or trityl group.Particularly preferred is a methyl group, an ethyl group, a tert-butylgroup, a 2-propenyl group, a benzyl group, a p-methoxybenzyl group or abenzhydryl group.

After completion of the reaction, conventional treatment is conducted toobtain a crude product of the compound of the formula (IV). The compoundof the formula (IV) may or may not be purified in accordance with aconventional method, and if necessary, reactions for removing protectinggroups such as a hydroxyl group, an amino group and a carboxyl group,are appropriately conducted to obtain a compound of the formula (I).

Removal of protecting groups may vary depending upon their types, butcan be conducted in accordance with the methods disclosed in aliterature (Protective Groups in Organic Synthesis, T. W. Greene, JohnWiley & Sons (1981)) or methods similar thereto, for example bysolvolysis employing an acid or a base, by chemical reduction employinga metal hydride complex or by catalytic reduction employing apalladium-carbon catalyst or Raney nickel.

Process 2

A compound of the formula (I-a): ##STR24## wherein ##STR25## A, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above, and X^(a) and Y^(a)are as defined below, can be prepared by reacting a compound of theformula (V): ##STR26## wherein X^(a) is a carbonyl group or a group ofthe formula --CHR^(a) -- (wherein R^(a) is as defined above), Z is aleaving group; and ##STR27## R^(1p) and R^(2p) are as defined above,with a compound of the formula (VI): ##STR28## wherein Y^(a) is anoxygen atom, a sulfur atom or a group of the formula --NR^(b) --(wherein R^(b) is as defined above); and ##STR29## A^(p), R^(3p),R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p) and R^(p) are as defined above,to obtain a compound of the formula (IV-a): ##STR30## wherein ##STR31##A^(p), X^(a), Y^(a), R^(1p), R^(2p), R^(3p), R^(4p), R^(5p), R⁶, R⁷,R^(8p), R^(9p) and R^(p) are as defined above, and, if necessary,removing any protecting group.

Process 2 is a process for preparing a compound of the formula (I)wherein --X--Y-- is a group of the formula --COO--, --COS--, --CONR^(b)--, --CHR^(a) O--, --CHR^(a) S-- or --CHR^(a) NR^(b) -- (wherein R^(a)and R^(b) are as defined above) i.e. a compound of the formula (I-a).

The reaction of the compound of the formula (V) with a compound of theformula (VI) is carried out usually by using 1 mol or an excess molaramount, preferably from 1 to 3 mols, of the compound of the formula (V),per mol of the compound of the formula (VI).

The reaction is conducted usually in an inert solvent. The inert solventmay, for example, be a halogenated hydrocarbon such as methylenechloride, chloroform, carbon tetrachloride, dichloroethane ortrichloroethylene; an ether such as ethyl ether, tetrahydrofuran ordioxane; an aromatic hydrocarbon such as benzene, toluene, chlorobenzeneor xylene; an aprotic polar solvent such as dimethylformamide,acetonitrile, acetone, ethyl acetate or hexamethylphosphoric triamide,or a mixture of such solvents.

The reaction temperature is usually from -70° C. to the boiling point ofthe solvent used for the reaction, preferably from -20° C. to 100° C.

The reaction time is usually from 5 minutes to 7 days, preferably from10 minutes to 24 hours.

The above reaction is preferably conducted in the presence of a base tofacilitate the reaction. Especially when Y^(a) in the formula (VI) isnot a group of the formula --NR^(b) --, it is necessary to carry out thereaction in the presence of an inorganic base such as sodium hydride,n-butyl lithium, sodium hydroxide, potassium hydroxide, calciumhydroxide, sodium carbonate, potassium carbonate or sodiumhydrogencarbonate, or an organic base such as triethylamine,N-ethyldiisopropylamine, pyridine, 4-dimethylaminopyridine orN,N-dimethylaniline.

The base is used usually in an amount of 1 mol or an excess molaramount, preferably from 1 to 5 mols, per mol of the compound of theformula (V).

The leaving group represented by Z in the formula (V) may, for example,be a halogen atom such as a chlorine atom, a bromine atom or an iodineatom, or an organic sulfonyloxy group such as a methanesulfonyloxygroup, a p-toluenesulfonyloxy group or a benzenesulfonyloxy group.

When a hydroxyl group is present on the group of the formula ##STR32##when a hydroxyl group, a lower hydroxyalkyl group, a carboxyl group or alower carboxyalkyl group is present on the saturated or unsaturatedaliphatic hydrocarbon group represented by A^(p), and when a hydroxylgroup, an amino group, a carboxyl group or a lower hydroxyalkyl group ispresent on the group of the formula ##STR33## it is preferred to conductthe reaction after protecting such a hydroxyl group, a lowerhydroxyalkyl group, an amino group, a carboxyl group or a lowercarboxyalkyl group appropriately by a hydroxyl-protecting group, anamino-protecting group or a carboxyl-protecting group and removing anyprotecting group after the reaction.

The hydroxyl-protecting group, the amino-protecting group and thecarboxyl-protecting group may be the protecting groups mentioned abovewith respect to process 1.

After completion of the reaction, a usual treatment is carried out toobtain a crude product of the compound of the formula (IV-a). Thecompound of the formula (IV-a) thus obtained may or may not be purifiedby a conventional method, and if necessary, reactions for removing thehydroxyl-, amino- and carboxyl-protecting groups may be carried out in aproper combination to obtain a compound of the formula (I-a).

The method for removing a protecting group varies depending upon thetype of the protecting group and the stability of the desired compound(I-a). However, removal of protecting groups can be appropriatelyconducted in accordance with the methods disclosed in theabove-mentioned literature or methods similar thereto.

Process 3

A compound of the formula (I-b): ##STR34## wherein ##STR35## A, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above, and X^(b) and Y^(b)are as defined below, can be prepared by reacting a compound of theformula (VII): ##STR36## wherein X^(b) is an oxygen atom, a sulfur atomor a group of the formula --NR^(b) -- (wherein R^(b) is as definedabove); and ##STR37## R^(1p) and R^(2p) are as defined above, with acompound of the formula (VIII): ##STR38## wherein Y^(b) is a carbonylgroup or a group of the formula --CHR^(a) -- (wherein R^(a) is asdefined above); and ##STR39## A^(p), Z, R^(3p), R^(4p), R^(5p), R⁶, R⁷,R^(8p), R^(9p) and R^(p) are as defined above, to obtain a compound ofthe formula (IV-b): ##STR40## wherein ##STR41## A^(p), X^(b), Y^(b),R^(1p), R^(2p), R^(3p), R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p) and R^(p)are as defined above, and, if necessary, removing any protecting group.

Process 3 is a process for preparing a compound of the formula (I)wherein --X--Y-- is a group of the formula --OCO--, --SCO--, --NR^(b)CO--, --OCHR^(a) --, --SCHR^(a) -- or --NR^(b) CHR^(a) -- (wherein R^(a)and R^(b) are as defined above) i.e. a compound of the formula (I-b).

This process can be conducted usually in an inert solvent, preferably inthe presence of a base, by using 1 mol or an excess molar amount,preferably from 1 to 3 mols, of the compound of the formula (VII), permol of the compound of the formula (VIII). The types of the inertsolvent and the base as well as the reaction conditions may be the sameas described above with respect to process 2. Accordingly, the reactionand the post-treatment after the reaction may preferably be carried outall in accordance with process 2.

Further, in the above processes 2 and 3, when X^(a) or Y^(b) is acarbonyl group, a compound wherein the group corresponding to Z is ahydroxyl group i.e. a compound wherein Z and the adjacent X^(a) or Y^(b)together represents a carboxyl group, can be used. In such a case, thereaction conditions, etc. are preferably in accordance with the reactionconditions for the reaction of the compound of the formula (II) with thecompound of the formula (III) in the above process 1.

Process 4

A compound of the formula (I-c): ##STR42## wherein ##STR43## A, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above, and R^(1a) andR^(2a) are as defined below, can be prepared by reacting a compound ofthe formula (IX): ##STR44## wherein R^(1a) is a hydrogen atom or a loweralkyl group; and ##STR45## R^(1p) and R^(2p) are as defined above, witha compound of the formula (X): ##STR46## wherein Q is atriphenylphosphonio group, a dimethoxyphosphoryl group or adiethoxyphosphoryl group; R^(2a) is a hydrogen atom or a lower alkylgroup; and ##STR47## A^(p), R^(3p), R^(4p), R⁵, R⁶, R⁷, R^(8p), R^(9p)and R^(p) are as defined above, to obtain a compound of the formula(XI): ##STR48## wherein ##STR49## A^(p), R^(1p), R^(2p), R^(3p), R^(4p),R^(5p), R⁶, R⁷, R^(8p), R^(9p), R^(p), R^(1a) and R^(2a) are as definedabove, and, if necessary, removing any protecting group.

Process 4 is a process for preparing a compound of the formula (I)wherein --X--Y-- is --CHR^(1a) CHR^(2a) -- (wherein each of R^(1a) andR^(2a) which are the same or different, is a hydrogen atom or a loweralkyl group) i.e. a compound of the formula (I-c).

The reaction of the compound of the formula (IX) with a compound of theformula (X) is carried out usually by employing equimolar amounts of thetwo reactants or using a slightly excess amount of one of them.

The reaction is carried out usually in an inert solvent. Such an inertsolvent may, for example, be an ether such as ethyl ether,tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene,toluene, chlorobenzene or xylene; an aprotic polar solvent such asdimethylformamide, acetonitrile, acetone, ethyl acetate orhexamethylphosphoric triamide; or a mixture of such solvents.

The reaction temperature is usually from -100° C. to the boiling pointof the solvent used for the reaction, preferably from -70° C. to 50° C.

The reaction time is usually from 5 minutes to 7 days, preferably from10 minutes to 24 hours.

Further, the above reaction can be conducted in the presence of a baseto facilitate the reaction. Especially when Q in the formula (X) is atriphenylphosphonio group, the reaction is preferably conducted in thepresence of a base such as sodium hydride, n-butyl lithium, sodiummethoxide, potassium tert-butoxide, sodium hydroxide or potassiumhydroxide.

Such a base is used in an amount of 1 mol or an excess molar amount,preferably from 1 to 5 mols per mol of the compound wherein Q is atriphenylphosphonio group.

The reaction of reducing the compound of the formula (XI) obtained inthe above step is usually preferably conducted by catalytic reductionemploying a palladium-carbon catalyst, a Raney nickel catalyst or aplatinum catalyst in an inert solvent.

The inert solvent may, for example, be an alcohol such as methanol,ethanol or propanol, or acetic acid.

The reaction temperature is usually from -20° C. to 100° C., preferablyfrom 0° C. to room temperature.

The reaction time is usually from 5 minutes to 7 days, preferably from10 minutes to 24 hours.

The hydrogen pressure in the catalytic reduction reaction is usuallypreferably from atmospheric pressure to 5 atm, and the amount of thecatalyst is usually from 0.01 to 1 mol, preferably from 0.05 to 0.2 mol,per mol of the starting material compound (XI).

After completion of the reaction, the product is subjected to a usualtreatment after removing any protecting group if such a protecting groupis present or directly if no such protecting group is present, to obtaina compound of the formula (I-c).

Removal of the protecting group and the post treatment may be conductedby the methods described with respect to the above process 1.

Process 5

A compound of the formula (I-c): ##STR50## wherein ##STR51## A, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(1a) and R^(2a) are as defined above, canbe obtained by reacting a compound of the formula (XII): ##STR52##wherein ##STR53## Q, R^(1p), R^(2p) and R^(1a) are as defined above,with a compound of the formula (XIII): ##STR54## wherein ##STR55##A^(p), R^(3p), R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p), R^(p) and R^(2a)are as defined above, to obtain a compound of the formula (XI):##STR56## wherein ##STR57## A^(p), R^(1p), R^(2p), R^(3p), R^(4p),R^(5p), R⁶, R⁷, R^(8p), R^(9p), R^(p), R^(1a) and R^(2a) are as definedabove, then reducing the compound of the formula (XI), and, ifnecessary, removing any protecting group.

Like process 4, process 5 is a process for producing a compound of theformula (I) wherein --X--Y-- is --CHR^(1a) CHR^(2a) -- (wherein R^(1a)and R^(2a) are as defined above) i.e. a compound of the formula (I-c).

Process 5 is equal to the reaction of process 4 wherein staring materialcompounds (IX) and (X) are replaced by the compounds (XIII) and (XII),respectively. Accordingly, the manner and conditions of the reaction maybe all in accordance with process 4.

Further, a compound of the formula (I-d): ##STR58## wherein ##STR59## A,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above, can beobtained by removing a protecting group, as the case requires, from acompound of the formula (XI-a): ##STR60## wherein ##STR61## A^(p),R^(1p), R^(2p), R^(3p), R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p) and R^(p)are as defined above, i.e. a compound of the formula (XI) wherein bothR^(1a) and R^(2a) are hydrogen atoms, among compounds of the formula(XI) obtainable as intermediates in the above processes 4 and 5.

Process 6

A compound of the formula (I-e): ##STR62## wherein ##STR63## X, Y, R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹², R¹³, p, q and r are as definedabove, can be prepared by oxidizing a compound of the formula (IV-e):##STR64## wherein R^(12p) is a hydrogen atom or a lower hydroxyalkyl orcarboxyl group which may be protected, R^(13p) is a hydrogen atom or ahydroxyl or carboxyl group which may be protected; and ##STR65## X^(p),Y^(p), R^(1p), R^(2p), R^(3p), R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p),R^(p), p, q and r are as defined above, and, if necessary, removing anyprotecting group.

Process 6 is a process for preparing a compound of the formula (I)wherein A is a group of the formula (b): ##STR66## wherein R¹², R¹³, p,q and r are as defined above, i.e. a compound of the formula (I-e).

The reaction of oxidizing the compound of the formula (IV-e) is usuallypreferably carried out in an inert solvent by using so-calledDess-Martin oxidation employing 12-I-5 triacetoxyperiodinane; so-calledSwern oxidation employing oxalyl chloride and dimethyl sulfoxide; asulfur trioxide-pyridine complex; pyridinium chlorochromate; activemanganese dioxide; or tetra-n-propylammonium perruthenate.

The inert solvent may, for example, be a halogenated hydrocarbon such asmethylene chloride, chloroform or dichloroethane; an ether such as ethylether, tetrahydrofuran or dioxane; an aprotic polar solvent such asacetonitrile, acetone, ethyl acetate or dimethyl sulfoxide; or a mixtureof such solvents.

The reaction temperature varies depending upon the type of the oxidizingagent, etc. However, it is usually from -100° C. to the boiling point ofthe solvent used for the reaction, preferably from -70° C. to 100° C.

The reaction time is usually from 5 minutes to 7 days, preferably from10 minutes to 24 hours.

After completion of the reaction, the product is subjected to usualtreatment after removing a protecting group when such a protecting groupis present, or directly when no such protecting group is present, toobtain the compound of the formula (I-e).

The removal of the protecting group and the post-treatment may beconducted in the same manner as described above with respect to process1.

Further, a compound corresponding to the compound of the formula (IV-e)to be used as the starting material in the above process 6, can beprepared, for example, by hydrolyzing a compound of the formula(IV-e-1): ##STR67## wherein ##STR68## X^(p), Y^(p), R^(1p), R^(2p),R^(3p), R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p), R^(12p), R^(13p), p, qand r are as defined above, in the presence of a base, to obtain acompound of the formula (IV-e-2): ##STR69## wherein M is a hydrogen atomor an alkali metal atom; and ##STR70## X^(p), Y^(p), R^(1p), R^(2p),R^(3p), R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p), R^(12p), R^(13p), p, qand r are as defined above, then reacting thereto a diazo compound ofthe formula

    +R.sup.pp -N.tbd.N

wherein R^(pp) is a lower alkyl group, a lower alkenyl group, an aralkylgroup or a lower alkoxycarbonylalkyl group, or an alkylating agent ofthe formula R^(pp) -Z¹ wherein R^(pp) and Z¹ are as defined above.

Isolation and purification of the compound of the formula (I), (I-a),(I-b), (I-c), (I-d) or (I-e), obtained by the above process can beconducted by a single use or a proper combination of conventionalseparating means such as column chromatography employing silica gel,adsorbent resin, etc., liquid chromatography, solvent extraction andrecrystallization-reprecipitation.

The compound of the formula (I), (I-a), (I-b), (I-c), (I-d) or (I-e) canbe converted to a pharmaceutically acceptable salt or ester by aconventional method. Reversely, the conversion from the salt or ester toa free carboxylic acid can also be conducted by a conventional method.

The compounds of the formulas (II), (III), (V), (VI), (VII), (VIII),(IX), (X), (XII) and (XIII) may be commercially available or can beprepared in accordance with the methods disclosed in literatures (J.Med. Chem., 10, 717 (1967); ibid., 725; J. Chem. Soc. Perkin I, 1636(1978); Chem. Lett., 191 (1980); ibid., 375 (1984); J.

Chem. Soc. Chem. Commun., 579 (1984); J. Am. Chem. Soc., 104, 5716(1982)) or methods similar thereto, or in accordance with the followingprocesses or the methods disclosed in Reference Examples. ##STR71##

In the above formulas, Q¹ is a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a chloroformyl group or anN-methoxy-N-methylcarbamoyl group; Q² is a halogen atom; Z¹ is a leavinggroup selected from the group consisting of a chlorine atom, a bromineatom, an iodine atom, a trifluoroacetoxy group, a methanesulfonyloxygroup, a trifluoromethanesulfonyloxy group and a p-toluenesulfonyloxygroup; and ##STR72## X^(p), Y^(p), R^(1p), R^(2p), R^(3p), R^(4p),R^(5p), R⁶, R⁷, R^(8p) and R^(9p) are as defined above.

By this process, the desired compound (II) can be prepared by reacting anitrile or a carboxylic acid derivative of the formula 1 with an alkyllithium of the formula 2 or an alkyl Grignard reagent (or an alkylGilman reagent) of the formula 3 to obtain a ketone compound 4, thenreacting an alkylating agent of the formula 5 to the ketone compound 4to produce a compound of the formula 6, then reacting the compound 6with an amine compound of the formula 7, followed by reduction.

The above reaction steps will be described in detail referring tosuitable reaction conditions, etc.

The first step of preparing the ketone compound 4 is conducted usuallyby reacting 1 mol or an excess molar amount, preferably from 1 to 5 molsof the alkyl lithium reagent 2 or the alkyl Grignard reagent (or thealkyl Gilman reagent in the case where the substituent Q¹ of thecompound 1 is a chloroformyl group) 3 to 1 mol of the starting materialcompound 1 in a solvent inert to the reaction such as tetrahydrofuran,ethyl ether or benzene, if necessary followed by hydrolysis under anacidic condition.

The reaction temperature is usually from -80° C. to the boiling point ofthe solvent used for the reaction, preferably from -70° C. to 50° C. Thereaction time is usually from 5 minutes to 48 hours, preferably from 30minutes to 24 hours.

When the substituent Q¹ in the formula of the starting material compound1 is a cyano group, it may be necessary to conduct a hydrolytic reactionunder an acidic condition after completion of the reaction, and such ahydrolytic reaction is conducted in e.g. methanol, ethanol,tetrahydrofuran or a solvent mixture thereof with water in the presenceof an acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonicacid.

The reaction temperature is usually from 0° C. to the boiling point ofthe solvent used for the reaction, and the reaction time is from 30minutes to 24 hours.

The step of preparing the compound of the formula 6 from the ketonecompound 4, can be conducted by reacting an equimolar amount or anexcess molar amount, preferably from 1 to 2 mols, of the alkylatingagent of the formula 5 to the ketone compound 4 in the presence of abase in an inert solvent which does not adversely affect the reaction orwithout using any solvent.

The inert solvent may, for example, be an ether such as ethyl ether,tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene,toluene or xylene; an aprotic polar solvent such as dimethylformamide,dimethyl sulfoxide or hexamethylphosphoric triamide, or a mixture ofsuch solvents.

The base to be used for this reaction, may, for example, be an alkalimetal hydride such as sodium hydride, lithium hydride or potassiumhydride; a lithium amide such as lithium amide, lithium diisopropylamideor lithium bis(trimethylsilyl)amide; an alkyl lithium such as methyllithium, butyl lithium or tert-butyl lithium; an alkali metal alkoxidesuch as sodium methoxide, sodium ethoxide or potassium tert-butoxide; oran alkali metal hydroxide such as sodium hydroxide, potassium hydroxideor lithium hydroxide.

The base is used usually in an amount of 1 mol or an excess molaramount, preferably from 1 to 5 mols, per mol of the starting materialalkylating agent 5.

The reaction temperature is usually from -100° C. to the boiling pointof the solvent used for the reaction, preferably from -80° C. to 100° C.The reaction time is usually from 10 minutes to 48 hours, preferablyfrom 30 minutes to 24 hours.

The step of preparing the desired compound (II) from the compound of theformula 6 can be conducted usually in an inert solvent such as methanol,ethanol, benzene, ethyl ether or tetrahydrofuran by reacting 1 mol or anexcess molar amount, preferably from 1 to 2 mols, of the amine compoundof the formula 7 to 1 mol of the compound of the formula 6 topreliminarily form an imine, which is subsequently reduced.

The reaction temperature in the process for forming the above imine isusually from 0° C. to the boiling point of the solvent used for thereaction, preferably from room temperature to 100° C. The reaction timeis usually from 5 minutes to 48 hours, preferably from 30 minutes to 24hours. After the formation of the imine, the reaction solution may beused as it is to the subsequent step of the reduction reaction, or thereaction solution may be distilled or subjected to a conventionalseparation means to isolate the imine compound, which is then subjectedto the subsequent reduction.

The reduction can be carried out by using a metal hydride complex suchas sodium borohydride, sodium cyanoborohydride or lithium aluminumhydride, or by catalytic reduction employing a palladium-carbon catalystor a Raney nickel catalyst.

When a metal hydride complex is used as a reducing agent, the reducingagent is used usually in an amount of 1 mol or an excess molar amount,preferably from 1 to 5 mols, per mol of the above imine.

For the reduction, an inert solvent, for example, an alcohol such asmethanol or ethanol; an ether such as dimethyl ether, ethyl ether,diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane,tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane,hexane, heptane or cyclohexane; or an aromatic hydrocarbon such asbenzene or toluene; or a mixture of such solvents, can be usedappropriately as a solvent depending upon the type of the reducingagent.

The reaction temperature is usually from 0° C. to room temperature, andthe reaction time is usually from 1 hour to 6 hours.

Further, in this process, it is also possible to react an alkylatingagent of the formula 5 to the nitrile or carboxylic acid derivative ofthe formula 1 to preliminarily produce an alkyl compound and then toreact an alkyl lithium of the formula 2 or an alkyl Grignard reagent (oran alkyl Gilman reagent) of the formula 3 to the alkyl compound toobtain a compound of the formula 6. Such a reaction can be conductedunder the conditions similar to the above Process A. Accordingly, thereaction conditions described for the above Process A may all be used asthe reaction conditions for this reaction.

The compounds of the formulas 1, 2, 3, 5 and 7 may be commerciallyavailable or can be produced by a proper combination, as the caserequires, of the methods disclosed in Reference Examples, orconventional methods or methods similar thereto. ##STR73## In the aboveformulas, ##STR74## X^(p), Y^(p), R^(1p), R^(2p), R^(3p), R^(4p),R^(5p), R⁶, R⁷, R^(8p) and R^(9p) are as defined above.

According to this process, the desired compound (II) can be prepared byreacting a reducing agent such as a metal hydride complex to a compoundof the formula 6 to obtain an alcohol compound 8 and reacting an aminecompound of the formula 7 to the alcohol compound 8.

The above reaction steps will be described in detail referring tosuitable reaction conditions, etc.

The reaction for reducing the compound of the formula 6 to the alcoholcompound 8 can be conducted usually by using a metal hydride complexsuch as sodium borohydride, diisobutyl aluminum hydride, lithiumaluminum hydride or lithium tri-sec-butylborohydride (L-selectride™), orby catalytic reduction employing e.g. a palladium-carbon catalyst or aRaney nickel catalyst, in an inert solvent which does not adverselyaffect the reaction.

When the metal hydride complex is used as the reducing agent, such areducing agent is used usually in an amount of 1 mol or an excess molaramount, preferably from 1 to 5 mols, per mol of the starting materialcompound 6.

The inert solvent to be used in this reaction may be suitably selecteddepending upon the type of the reducing agent.

For example, when the reducing agent is sodium borohydride, an inertsolvent, such as an alcohol such as methanol or ethanol; an ether suchas dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aproticpolar solvent such as dimethylformamide or dimethylacetamide, or water,or a solvent mixture thereof, may be used, and particularly preferred isan alcohol such as methanol or ethanol.

For example, when the reducing agent is diisobutyl aluminum hydride, aninert solvent, such as an ether such as dimethyl ether, ethyl ether,diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane,tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane,hexane, heptane or cyclohexane; an aromatic hydrocarbon such as benzeneor toluene; methylene chloride, or a solvent mixture thereof, may beused, and particularly preferred is toluene or methylene chloride.

For example, when the reducing agent is lithium aluminum hydride orlithium tri-sec-butylborohydride, an inert solvent, such as an ethersuch as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether,dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aliphatichydrocarbon such as pentane, hexane, heptane or cyclohexane; or anaromatic hydrocarbon such as benzene or toluene, or a solvent mixturethereof, may be used, and particularly preferred is ethyl ether ortetrahydrofuran.

For the catalytic reduction, the solvent is preferably an alcohol suchas methanol or ethanol.

The reaction temperature and the reaction time vary depending upon thestability and the susceptibility to the reduction reaction of thestarting material ketone compound 6, the type of the reducing agent andthe type of the solvent. However, the reaction temperature is usuallyfrom -80° C. to 100° C., preferably from -70° C. to 40° C., and thereaction time is usually from 5 minutes to 2 days, preferably from 30minutes to 24 hours.

The step of preparing the desired compound (II) from a compound of theformula 8 can be carried out by reacting a sulfonating agent such asmethanesulfonyl chloride to the alcohol compound of the formula 8 in thepresence of a base, or reacting a halogenating agent such as thionylchloride or phosphorus tribromide thereto, to convert the hydroxyl groupin the formula to a leaving group, followed by reacting an aminecompound of the formula 7.

The reaction for introducing the leaving group can be conducted usuallyby reacting 1 mol or an excess molar amount, preferably from 1 to 2mols, of a sulfonating agent and a base such as triethylamine to 1 molof the alcohol compound 8 in an inert solvent such as methylenechloride, chloroform, benzene, tetrahydrofuran or ethyl acetate, orusing 1 mol or an excess molar amount, preferably from 1 to 5 mols, of ahalogenating agent.

The reaction temperature is usually from -70° C. to the boiling point ofthe solvent used for the reaction, preferably from -20° C. to 80° C.,and the reaction time is usually from 5 minutes to 48 hours, preferablyfrom 30 minutes to 24 hours.

Then, the step of reacting an amine compound 7 to the compound havingthe leaving group introduced, obtained by the above reaction, can beconducted usually by employing 1 mol or an excess molar amount,preferably from 1 to 50 mols, of the amine compound 7 per mol of thestarting compound having the leaving group, in an inert solvent such asmethylene chloride, chloroform, benzene, ethyl ether or tetrahydrofuran.

If necessary, this reaction can be conducted in the presence of a baseother than the amine compound of the formula 7.

As such a base, an inorganic base such as sodium hydroxide, potassiumhydroxide, calcium hydroxide, sodium carbonate, potassium carbonate orsodium hydrogencarbonate, or an organic base such as triethylamine,N-ethyldiisopropylamine, pyridine or N,N-dimethylaniline may, forexample, be mentioned.

Such a base is used usually in an amount of 1 mol or an excess molaramount, preferably from 1 to 5 mols, per mol of the starting materialcompound.

The reaction temperature is usually from -50° C. to 150° C., preferablyfrom -20° C. to 100° C., and the reaction time is usually from 5 minutesto 7 days, preferably from 10 minutes to 24 hours. ##STR75##

In the above formulas, ##STR76## X^(p), Y^(p), R^(1p), R^(2p), R^(3p),R^(4p), R^(5p), R⁶, R⁷, R^(8p) and R^(9p) are as defined above.

According to this process, the desired compound (II) can be prepared byfirstly reacting diethyl azodicarboxylate, triphenylphosphine andphthalimide (or hydrogen azide or diphenylphosphoryl azide) or reactinga sulfonylation agent such as methanesulfonyl chloride in the presenceof a base such as triethylamine, then reacting phthalimide (or sodiumazide) in the presence of a base, to the alcohol compound of the formula8, to obtain a phthalimide-protected form (or an azide compound) of theamine compound 9, then reacting hydrazine (or a reducing agent) toremove the phthalimide group (or reduce the azide group) to obtain anamine product of the formula 9, and finally reacting a compound of theformula 10 to the compound 9, followed by reduction.

The above reaction steps will be described in detail referring tosuitable reaction conditions, etc.

For the step of producing the amine compound of the formula 9 from thealcohol compound 8, various synthetic methods and reaction conditionswell known in organic synthetic chemistry for converting alcoholcompounds to amines, may be employed. For example, it is preferred toemploy a Mitsunobu reaction using diethyl azodicarboxylate,triphenylphosphine and phthalimide (or hydrogen azide ordiphenylphosphoryl azide) or a method which comprises sulfonylation witha sulfonylation agent such as methanesulfonyl chloride in the presenceof a base such as triethylamine, then reacting phthalimide (or sodiumazide) in the presence of a base, and then treating the obtainedphthalimide compound with hydrazine (or reducing the azide compound).

The above reactions are conducted usually in a solvent inert to thereaction. The inert solvent may, for example, preferably betetrahydrofuran, dimethoxyethane, benzene or toluene in the case of theabove-mentioned Mitsunobu reaction; methylene chloride, chloroform,tetrahydrofuran, benzene, ethyl acetate or dimethylformamide in the caseof the sulfonylation followed by the reaction with phthalimide (orsodium azide); an alcohol such as methanol or ethanol in the next stepof the phthalimide-removing reaction with hydrazine; an ether such asethyl ether or tetrahydrofuran in the case where a metal hydride complexis used as the reducing agent in the reduction reaction of the azidecompound; water-containing tetrahydrofuran in the case where phosphinereduction is conducted with triphenylphosphine or the like; and analcohol such as methanol or ethanol in the reduction by catalyticreduction.

With respect to the amounts of the reagents to be used, in the aboveMitsunobu reaction, each of diethyl azodicarboxylate, triphenylphosphineand phthalimide (or hydrogen azide or diphenylphosphoryl azide) is usedin an amount of 1 mol or an excess molar amount, preferably from 1 to 5mols, per mol of the starting material alcohol compound 8. In thereaction with the phthalimide (or sodium azide) after the sulfonylation,the sulfonylation agent such as methanesulfonyl chloride is used in anamount of 1 mol or an excess molar amount, preferably from 1 to 2 mols,per mol of the alcohol compound 8, and the base such as triethylamineused at that time is usually in an amount of 1 mol or an excess molaramount, preferably from 1 to 2 mols, per mol of the sulfonylation agent.In the next step of the reaction with phthalimide (or sodium azide) inthe presence of a base, 1 mol or an excess molar amount, preferably from1 to 5 mols of each of phthalimide and the base (or sodium azide) isused per mol of the starting material sulfonylation agent. Here, thebase to be used together with phthalimide is preferably sodium carbonateor potassium carbonate. Otherwise, without using such a base, a sodiumsalt or a potassium salt of phthalimide may be used by itself. Then, inthe reaction for removing the phthalimide group with hydrazine,hydrazine is used in an amount of 1 mol or an excess molar amount,preferably from 1 to 10 mols, per mol of the phthalimide compound as thestarting material compound. In the reduction of the azide compound witha metal hydride complex or with triphenylphosphine, the reducing agentis used usually in an amount of 1 mol or an excess molar amount,preferably from 1 to 2 mols, per mol of the azide compound.

In the case of the above Mitsunobu reaction, the reaction temperature isusually from -70° C. to 100° C., preferably from -20° C. to 50° C., andthe reaction time is usually from 5 minutes to 48 hours, preferably from30 minutes to 24 hours. In the reaction for removing the phthalimidegroup by hydrazine, the reaction temperature is usually from 0° C. tothe boiling point of the solvent used for the reaction, preferably fromroom temperature to 100° C., and the reaction time is usually from 5minutes to 48 hours, preferably from 30 minutes to 24 hours. In thereaction for converting the azide compound to the amine compound byreduction, when a metal hydride complex is used as the reducing agent,the reaction temperature is usually from -70° C. to 150° C., preferablyfrom -20° C. to 50° C., and the reaction time is usually from 5 minutesto 48 hours, preferably from 10 minutes to 10 hours. Whentriphenylphosphine is used as the reducing agent, the reactiontemperature is usually from room temperature to the boiling point of thesolvent used for the reaction, preferably from 30° C. to 100° C., andthe reaction time is usually from 10 minutes to 48 hours, preferablyfrom 30 minutes to 24 hours. Further, in the case of the reduction bycatalytic reduction, the reaction temperature is usually from 0° C. to100° C., preferably from room temperature to 50° C., and the reactiontime is usually from 10 minutes to 48 hours, preferably from 10 minutesto 24 hours.

The step for producing the desired compound (II) from the compound ofthe formula 9 is carried out usually by preliminarily forming an imineby reacting 1 mol or an excess molar amount, preferably from 1 to 2 molsof the compound of the formula 10 to 1 mol of the compound of theformula 9 in an inert solvent such as methanol, ethanol, benzene, ethylether or tetrahydrofuran, and then reducing it.

This step can be carried out in the same manner as the step forproducing the desired compound (II) from the compound of the formula 6in the above process A. Accordingly, with respect to the reactionconditions, etc., similar conditions may be employed.

Further, the compound of the formula 10 may be commercially available orcan be produced by a proper combination, as the case requires, of themethods disclosed in Reference Examples, or conventional methods ormethods similar thereto. ##STR77##

In the above formulas, R¹⁴ means a hydroxyl-protecting group when Y^(a)is an oxygen atom; a mercapto-protecting group when Y^(a) is a sulfuratom; or an amino- or imino-protecting group when Y^(a) is a group ofthe formula --NR^(b) -- (wherein R^(b) is as defined above); and##STR78## A^(p), Y^(a), Z¹, R^(3p), R^(4p), R^(5p), R⁶, R⁷, R^(8p),R^(9p) and R^(p) are as defined above.

According to this process, the desired compound (VI) can be prepared byfirstly reacting an alkylating agent of the formula 11 to a ketonecompound of the formula 4 to obtain a compound of the formula 12,reacting a reducing agent such as a metal hydride complex to thecompound 12 to obtain an alcohol compound, then reacting diethylazodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azideor diphenylphosphoryl azide) or reacting a sulfonylation agent such asmethanesulfonyl chloride in the presence of a base such astriethylamine, and then reacting phthalimide (or sodium azide) in thepresence of a base, to obtain a phthalimide-protected form (or an azidecompound) of the amine compound 13, then reacting hydrazine (or areducing agent) to remove the phthalimide group (or reduce the azidegroup) to obtain an amine compound of the formula 13, reacting acompound of the formula 10 to the compound 13, followed by reduction toobtain a compound of the formula 14, reacting a carboxylic acid of theformula (III) or its reactive derivative to the compound 14, and finallyselectively removing the protecting group represented by R¹⁴.

The step of producing a compound of the formula 12 from a ketonecompound of the formula 4, can be carried out in the same manner as thestep of producing the compound of the formula 6 from the ketone of theformula 4 in the above process A. Accordingly, with respect to thereaction conditions, etc., similar conditions may be employed.

When R¹⁴ is a hydroxyl-protecting group, such a hydroxyl-protectinggroup may be the one disclosed above with respect to process 1.

When R¹⁴ is a mercapto-protecting group, the hydroxyl-protecting groupdisclosed above with respect to process 1 can be used as such amercapto-protecting group.

When R¹⁴ is an amino- or imino-protecting group, such an amino- orimino-protecting group may be the amino- or imino-protecting groupdisclosed above with respect to process 1.

In the step of producing the amine compound of the formula 13 afterreacting a reducing agent such as a metal hydride complex to thecompound of the formula 12 to obtain an alcohol compound, the step ofconverting the compound of the formula 12 to the alcohol compound can becarried out in the same manner as the step of reducing the compound ofthe formula 6 to the alcohol compound 8 in the above process B.Accordingly, with respect to the reaction conditions, etc., similarconditions may be employed. Further, the step of producing an aminecompound of the formula 13 from the obtained alcohol, can be carried outin the same manner as in the step of producing the amine compound 9 fromthe alcohol compound of the formula 8 in the above process C.Accordingly, with respect to the reaction conditions, etc., similarconditions may be employed.

The step of producing a compound of the formula 14 from the aminecompound of the formula 13, can be carried out in the same manner as inthe step of producing a compound of the formula (II) from the amine ofthe formula 9 in the above process C. Accordingly, with respect to thereaction conditions, etc., similar conditions may be employed.

In the step of producing the desired compound (VI) from the compound ofthe formula 14, the reaction of the compound of the formula 14 with thecarboxylic acid of the formula (III) or its reactive derivative, can becarried out in the same manner as the reaction of the compound of theformula (II) with the carboxylic acid of the formula (III) or itsreactive derivative in the above process 1. Accordingly, with respect tothe reaction conditions, etc., similar conditions may be employed.

For the step of selectively removing the protective group represented byR¹⁴ from the compound obtained by the above reaction, various methodsmay suitably be selected depending upon the type and the characteristicsof the protecting group. Namely, utilizing the difference in thestability against an acid, a base or reduction between R¹⁴ and otherprotecting groups, the protecting group can selectively be removed by aconventional means such as an acid, a base or reduction. With respect tospecific conditions for such a reaction, the methods disclosed in knownliteratures, such as "Protective Groups in Organic Synthesis, T. W.Greene, John Siley & Sons (1981)", may, for example, be used.

Further, the compound of the formula 11 may be commercially available,or may be produced by a proper combination, as the case requires, of themethods disclosed in Reference Examples, or conventional methods ormethods similar thereto. ##STR79##

In the above formulas, R¹⁵ is a protected carboxyl group or a group ofthe formula R^(a) --C(OR^(p1)) (OR^(p2))-- (wherein each of R^(p1) andR^(p2) which are the same or different, is a methyl group or an ethylgroup, or R^(p1) and R^(p2) together represent an ethylene group, andR^(a) is as defined above); R¹⁶ is a hydroxyl group or a group of theformula R^(a) (wherein R^(a) is as defined above); and ##STR80## A^(p),Z, Z¹, R^(3p), R^(4p), R^(5p), R⁶, R⁷, R⁸ P, R^(9p), R^(a) and R^(p) areas defined above.

According to this process, the desired compound (VIII-a) can be preparedby firstly reacting an alkylating agent of the formula 15 to a ketonecompound of the formula 4 to obtain a compound of the formula 16,reacting a reducing agent such as a metal hydride complex to thecompound 16 to obtain an alcohol compound, then reacting diethylazodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azideor diphenylphosphoryl azide), or reacting a sulfonylation agent such asmethanesulfonyl chloride in the presence of a base such as triethylamineand then reacting phthalimide (or sodium azide) in the presence of abase, to obtain a phthalimide-protected form (or an azide compound) ofthe amine compound 17, then reacting hydrazine (or a reducing agent) toremove the phthalimide group (or reduce the azide group) to obtain anamine compound of the formula 17, reacting a compound of the formula 10to the compound 17, followed by reduction to obtain a compound of theformula 18, reacting a carboxylic acid of the formula (III) or itsreactive derivative to the compound 18, then selectively removing theprotecting group at R¹⁵ to obtain a compound of the formula 19, reactinga reducing agent to the compound 19 to obtain a compound of the formula20, and finally introducing a leaving group to the compound 20.

The respective steps up to the production of the compound of the formula19 from the ketone compound of the formula 4 can be carried out in thesame manner as the respective steps for the production of the compoundof the formula (VI) from the ketone compound of the formula 4 in theabove process D. Accordingly, with respect to the reaction conditions,etc., the same conditions as in the corresponding respective steps canbe employed.

The step of reacting a reducing agent to the compound of the formula 19to obtain the compound of the formula 20, can be conducted in the samemanner as the reduction method employing e.g. sodium borohydride as areducing agent in the step of reducing the compound of the formula 6 toan alcohol compound 8 in the above process B. Accordingly, with respectto the reaction conditions, etc., similar conditions can be employed.

The step of producing the desired compound (VIII-a) by introducing aleaving group to the compound of the formula 20 can be carried out inthe same manner as in the method of introducing a leaving group to thecompound of the formula 8 in the above process B by using, for example,a halogenating agent such as thionyl chloride, phosphorus trichloride,phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide,oxalyl chloride or phosgene, or a sulfonating agent such asmethanesulfonyl chloride, p-toluenesulfonyl chloride or benzenesulfonylchloride. Accordingly, with respect to the reaction conditions, etc.,similar conditions may be employed.

Further, the compound of the formula 15 may be commercially available,or can be produced by a proper combination, as the case requires, of themethods disclosed in Reference Examples, or conventional methods ormethods similar thereto. ##STR81## In the above formulas, ##STR82##A^(p), Z, R^(3p), R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p) and R^(p) areas defined above.

According to this process, the desired compound (VIII-b) can be preparedby introducing a leaving group to the compound of the formula 19-a inthe same manner and conditions as the method of introducing a leavinggroup to the compound of the formula 20 in the above process E.##STR83## In the above formulas, ##STR84## A^(p), Q, Z, R^(3p), R^(4p),R^(5p), R⁶, R⁷, R^(8p), R^(9p), R^(a) and R^(p) are as defined above.

According to this process, the desired compound (X) can be prepared byreacting triphenylphosphine, trimethyl phosphite or triethyl phosphite,to the compound of the formula (VIII-a).

When a triphenylphosphine is reacted, the above reaction is carried outusually in an inert solvent which does not affect the reaction. As suchan inert solvent, toluene or xylene is, for example, preferred.

The triphenylphosphine is used usually in an amount of 1 mol or anexcess molar amount, preferably from 1 to 5 mols, per mol of thecompound (VIII-a).

The reaction temperature is usually from room temperature to the boilingpoint of the solvent used for the reaction, preferably from 80° C. to150° C. The reaction time is usually from 5 minutes to 7 days,preferably from 1 hour to 24 hours.

Likewise, when trimethyl phosphite or triethyl phosphite is reacted tothe compound (VIII-a), the above reaction is conducted usually in aninert solvent which does not affect the reaction, or more preferably, anexcess trimethyl phosphite or triethyl phosphite is used as both thesolvent and the reactant.

The reaction temperature is usually from room temperature to the boilingpoint of the solvent for the reaction, preferably from 80° C. to 150°C., and the reaction time is usually from 5 minutes to 7 days,preferably from 1 hour to 24 hours.

A compound of the formula (XII): ##STR85## wherein ##STR86## Q, R^(1p),R^(2p) and R^(1a) are as defined above, can be prepared from a compoundof the formula (XIV): ##STR87## wherein ##STR88## Z, R^(1p), R^(2p) andR^(1a) are as defined above, in accordance with process G.

Further, the compound of the formula (XIV) may be commerciallyavailable, or can be prepared by a proper combination, as the caserequires, of the methods disclosed in Reference Examples, orconventional methods or methods similar thereto.

Further, the formula (XIII): ##STR89## wherein ##STR90## A^(p), R^(3p),R^(4p), R^(5p), R⁶, R⁷, R^(8p), R^(9p), R^(p) and R^(2a) are as definedabove, is substantially the same as the formula 19 in the above processE, wherein R¹⁶ is a group of the formula R^(a). Accordingly, thecompound of the formula (XIII) can be prepared by the above process E.##STR91##

In the above formulas, each of R¹⁷ and R¹⁹ which are the same ordifferent, is a hydrogen atom, a lower alkyl group, an aryl group or anaralkyl group; each of R²⁰ and R²¹ which are the same or different, is acarboxyl-protecting group; and R¹⁸ is a tert-butyl group, a benzylgroup, a benzhydryl group or a trityl group.

Process H is a process for preparing a carboxylic acid derivative of theformula (III-a) among the compounds of the above formula (III).

According to this process, the desired carboxylic acid derivative(III-a) can be prepared by conducting a so-called Michael additionreaction which comprises reacting a maleic acid derivative or a fumaricacid derivative of the formula 22 to an ester derivative having areadily removable carboxyl-protecting group R¹⁸, represented by theformula 21, in the presence of a base, and then removing thecarboxyl-protecting group R¹⁸ from the obtained Michael addition product23 under a mild condition.

As the carboxyl-protecting group for R²⁰ and R²¹, a lower alkyl groupsuch as a tert-butyl group, or a benzhydryl group, is preferred.

The protecting group R¹⁸ is preferably the one which can readily beremoved under a mild condition of catalytic reduction or weakly acidiccondition and which is stable under the Michael addition reactioncondition, such as a tert-butyl group, a benzyl group, a benzhydrylgroup or a trityl group.

The above Michael addition reaction can be conducted by reacting thecompound of the formula 22 in an amount of 1 mol or an excess molaramount, preferably from 1 to 2 mols, to 1 mol of the compound of theformula 21 in the presence of a base such as sodium hydride, butyllithium, lithium diisopropylamide or lithium bis(trimethylsilyl)amideusually in an inert solvent such as benzene, ethyl ether ortetrahydrofuran.

Such a base is used usually in an amount of 1 mol or a slightly excessmolar amount, preferably from 1 to 1.5 mols, per mol of the compound ofthe formula 22.

The reaction temperature is usually from -100° C. to 100° C., preferablyfrom -80° C. to room temperature, and the reaction time is usually from5 minutes to 24 hours, preferably from 10 minutes to 10 hours.

The reaction conditions for the reaction for removing the protectinggroup from the compound of the formula 23 to form the desired carboxylicacid derivative (III-a), vary depending upon the type of the protectinggroup, etc. For example, when the protecting group is a tert-butylgroup, a benzhydryl group or a trityl group, a method may be employedwherein the compound is treated with an acid such as acetic acid, formicacid, trifluoroacetic acid or hydrochloric acid, preferably within atemperature range of from -20° C. to 50° C. for from 10 minutes to 24hours in the absence of a solvent or usually in an inert solvent such asmethylene chloride, anisole, tetrahydrofuran, methanol or ethanol or asolvent mixture thereof with water.

For example, when the protecting group is a benzyl group, a benzhydrylgroup or a trityl group, a method may be employed wherein the compoundis catalytically reduced with a catalyst such as a palladium-carboncatalyst or a Raney nickel catalyst preferably under a hydrogen pressureof from 1 to 20 kg/cm² preferably within a temperature range of from 0°C. to 40° C. for from 10 minutes to 24 hours usually in an inert solventsuch as methanol, ethanol, dioxane, water or acetic acid, or a solventmixture thereof.

Among compounds of the formula (III-a), an optically active compound ofthe formula (III-b¹): ##STR92## or the formula (III-b²): ##STR93##wherein each of R¹⁸ and R¹⁹ which are the same or different, is acarboxyl-protecting group, can be obtained by reacting a racemic mixtureof the compound of the formula (III-b): ##STR94## wherein R¹⁸ and R¹⁹are as defined above, with cinchonidine or quinine to obtain a mixtureof two diastereomers, then separating and collecting either one of thediastereomers by utilizing the difference in the solubility as betweenthe two diastereomers, followed by recovering the free carboxylic acidby treating with an acid.

Separation of the diastereomer mixture may be conducted in an organicsolvent such as carbon tetrachloride or isopropyl ether. Usually, themixture of the diastereomers is dissolved in a solvent in a hot state,and the solution is gradually cooled to utilize the solubilitydifference for separation of the diastereomers.

Further, either one of the diastereomers thus obtained is treated withan acid such as hydrochloric acid to obtain an optically active compoundof the formula (III-b¹) or (III-b²).

The compounds of the formula 21 and 22 may be commercially available orcan be produced by a proper combination, as the case requires, of themethods disclosed in Reference Examples, or conventional methods ormethods similar thereto. ##STR95## In the above formulas, W is ##STR96##(wherein ##STR97## X^(p), Y^(p), R^(1p) and R^(2p) are as definedabove), R¹⁴ --Y^(a) -- (wherein Y^(a) and R¹⁴ are as defined above) orR¹⁵ (wherein R¹⁵ is as defined above); R^(s) is a hydrogen atom or amethyl group; R^(t) is a lower alkyl group, an aryl group or a loweralkenyl group; and ##STR98## R^(3p), R^(4p), R^(5p) and R⁶ are asdefined above.

Process I is a process for preparing an optically active substance 27 or28 of an alcohol compound 24 obtainable as the above formula 8 or areduction product of the formula 12 or 16.

According to this process, the desired optically active alcoholcompounds 27 and 28 can be prepared by reacting a vinyl ester derivativeof the formula 25 to a racemic alcohol derivative of the formula 24 inthe presence of a lipase, separating the obtained optically active esterderivative 26 and the optically active alcohol derivative, and thenhydrolyzing the ester group with respect to the optically active esterderivative 26.

R^(t) of the vinyl ester derivative of the formula 25 is preferably alower alkyl group such as a methyl group or an ethyl group; an arylgroup such as a phenyl group or a naphthyl group; or an aralkyl groupsuch as a benzyl group or a 2-phenylethyl group. Particularly preferredis a methyl group, i.e. a case wherein the compound of the formula 25 isvinyl acetate or isopropenyl acetate.

The above optical resolution reaction by lipase can be conducted usuallyin an inert solvent such as methylene chloride, chloroform, ethyl ether,tetrahydrofuran, benzene, toluene, hexane, heptane or acetonitrile, orby using the starting material vinyl ester derivative of the formula 25itself as the solvent.

The vinyl ester derivative 25 is used usually in an amount of 1 mol orin a large excess molar amount, preferably from 1 to 100 mols, per molof the starting material compound 24, and the amount of the lipase asthe catalyst is from 0.01 to 100%, preferably from 0.1 to 20%, byweight, relative to the compound 24.

The type of the lipase is preferably a lipase derivative fromPseudomonas sp. such as Toyothium LIP™ (manufactured by Toyobo).

Further, the above enzymatic reaction tends to be accelerated, when thereaction is carried out in the presence of a base. As a base to be usedfor this purpose, an organic base such as triethylamine ordiisopropylethylamine, is preferred.

The base is used usually in an amount of 0.01 mol or a slightly excessmolar amount, preferably from 0.1 to 1.5 mols, relative to the startingmaterial compound 24.

The reaction temperature is usually from 0° C. to 50° C., preferablyfrom room temperature to 40° C. The reaction time is usually from 30minutes to 7 days, preferably from 1 hour to 48 hours.

The hydrolytic reaction of the ester of the formula 26 can be conductedby a common method well known in the organic synthetic chemistry underan acidic or basic condition.

To demonstrate the usefulness of the compounds of the present invention,50% inhibitory concentrations (IC₅₀ values) of the compounds of thepresent invention against the protein-farnesyl transferase (PFT)activities, were obtained.

Inhibitory Activities Against Protein-Farnesyl Transferase

(1) Preparation of PFT

PFT was separated in such a manner that a soluble fraction of rat'sbrain was fractionated by means of 30%-50% saturated ammonium sulfate,further dialyzed and then subjected to column chromatography byQ-cephalose™ (manufactured by Pharmacia) (Reiss et al, Cell, vol. 62, p.81-88 (1990)).

(2) Method for measuring PFT activities

Measurement of PFT activities was conducted by using, as a prenylacceptor, H-ras protein or a substance that biotin was added toN-terminal of a peptide corresponding to a 7 amino acid residue at Cterminal of K-rasB protein (biotin-added Lys-Thr-Ser-Cys-Val-Ile-Met)and, as a prenyl doner, ³ H!-labeled farnesylpyrophosphate (FPP) (Reisset al, Methods: A Companion to a Methods in Enzymology, vol. 1, No. 3,p. 241-245 (1990)).

The ³ H!-labeled farnesylpyrophosphate (22.5 Ci/mmol) was purchased fromNew England Nuclear Co. Non-labeled farnesylpyrophosphate was chemicallysynthesized from ditriethylammonium phosphate, trans-trans-farnesol andtrichloroacetonitrile and purified by XAD-2-resin column anddiethylaminoethylcellulose (Cornforth et al, Methods in Enzymology, vol.15, p. 385-390 (1969)).

H-ras protein was expressed in Escherichia coli and purified (Gibbs etal, Proc. Natl. Acad. Sci., vol. 81, p. 5704-5708 (1984)).

The PFT reaction solution containing H-ras protein as the prenylacceptor was 25 μl, and its composition was 50 mM Hepes pH7.5/50 μMZnCl₂ /5 mM MgCl₂ /20 mM KCl/5mM DTT/0.6 μM all trans ³H!-farnesylpyrophosphate/25 μM H-ras protein/PFT derived from rat brain(Q-sephalose fraction). The reaction temperature was 37° C., thepreincubation time was 10 minutes, and the reaction time was 20 minutes.

The PFT reaction solution containing biotin-addedLys-Thr-Ser-Cys-Val-Ile-Met as the prenyl acceptor, was 25 μl, and itscomposition was 50 mM tris-Cl pH7.5/50 μM ZnCl₂ /5 mM MgCl₂ /20 mM KCl/1mM DTT/0.2% n-octyl-β-D-glucopyranoside/0.6 μM all trans ³H!-farnesylpyrophosphate/3.6 μM biotin-addedLys-Thr-Ser-Cys-Val-Ile-Met/PFT derived from rat brain (Q-sephalosefraction). The reaction temperature was 37° C., the preincubation timewas 10 minutes, and the reaction time was 20 minutes.

The enzymatic reaction product containing H-ras protein as the prenylacceptor, was analyzed by SDS-PAGE (sodium dodecylsulfate/polyacrylamidegel electrophoresis). The ³ H!-labeled enzymatic reaction product wasboiled for 3 minutes in a buffer solution containing 2% SDS/50 mMTris-Cl pH6.8/10% sucrose/5% 2-mercaptoethanol, then subjected toelectrophoresis with a slab gel of 12% polyacrylamide, whereby the ³H!-labeled H-ras protein was fluorography-enhanced by EN³ HANCE™(manufactured by New England Nuclear Co.) and then visualized byautoradiography (James et al, Science, vol. 260, No. 25, p. 1937-1942(1993)).

The measurement of PFT activities using H-ras protein as the prenylreceptor, was also analyzed by a rapid separate method. The mixedsolution for measurement wherein no prenyl doner was present, waspreincubated and a prenyl group transferring reaction was initiated byan addition of ³ H!-FPP and terminated at an appropriate time by anaddition of 0.5 ml of 4% SDS. Further, 0.5 ml of 30% trichloroaceticacid was added thereto and thoroughly mixed. Then, the reaction solutionwas left to stand at 4° C. for 60 minutes to let H-ras proteinprecipitate. This reaction solution was subjected to filtration underreduced pressure by Whatman GF/B filter. The filter was washed 6 timeswith 2 ml of 6% trichloroacetic acid, and mixed with 8 ml ofscintillation cocktail (Clearsol I™, manufactured by Nacalai TesqueCo.). Then, counting was carried out by a Beckmann TRI-CARB2500TRscintillation counter.

Measurement of PFT activities was also carried out by using biotin-addedLys-Thr-Ser-Cys-Val-Ile-Met as the prenyl acceptor. The mixed solutionfor measurement containing biotin-added Lys-Thr-Ser-Cys-Val-Ile-Met asthe prenyl acceptor and containing no prenyl doner, was preliminarilythermally equilibrated, and then a prenyl group transferring reactionwas initiated by an addition of ³ H!-FPP and terminated at anappropriate time by an addition of 0.2 ml of 2 mg/ml bovine serumalbumin/2% sodium dodecylsulfate/150 mM NaCl. Further, 0.02 ml of avidinagarose (Pierce) was added thereto, and the mixture was shaked for 30minutes to let the ³ H!-farnesyl group-transferred biotin-addedLys-Thr-Ser-Cys-Val-Ile-Met sufficiently bond to the avidin agarose.Then, avidin agarose was washed four times with 1 ml of 2 mg/ml bovinserum albumin (BSA)/4% sodium dodecylsulfate/150 mM NaCl, and mixed with1 ml of scintillation cocktail (Clearsol I™, manufactured by NacalaiTesque). Then, counting was carried out by a Beckmann TRI-CARB2500TRscintillation counter.

The biotin-added Lys-Thr-Ser-Cys-Val-Ile-Met heptapeptide used as anartificial substrate, was synthesized in a solid phase by an Appliedbiosystems model 431A peptide synthesizer, and an α-amino terminal ofthe solid phase Lys-Thr-Ser-Cys-Val-Ile-Met heptapeptide which was boundto a resin, was biotin-modified by N-hydroxysuccinimide biotin, then cutoff from the resin and purified by reversed phase high performanceliquid chromatography (HPLC).

The addition of the compound of the present invention to the PFTreaction system was carried out by preliminarily adding dimethylsulfoxide in an amount of 1% by volume (0.25 μl) of the reactionsolution.

The 50% inhibitory concentrations (IC₅₀ values) of the compounds of thepresent invention against PFT activities, were obtained, and the resultsare shown in the following Table.

                  TABLE 1    ______________________________________    50% inhibitory concentrations    against PFT activities           Compound                   IC.sub.50 (nM)    ______________________________________           Example 1                   0.6           Example 10                   1.8    ______________________________________

PHARMACOLOGICAL TEST EXAMPLE 2 (Inhibitory Activities AgainstFarnesyl-Modification of Ras Protein)

Using the compounds of the present invention, inhibitory activitiesagainst farnesyl-modification of Ras protein in NIH3T3 cells transformedby activated ras gene, were measured.

The NIH3T3 cells transformed by activated ras gene, were seeded on aculture plate and cultured for 3 days. Then, a compound of the presetinvention in a predetermined concentration was added to the culture. Inaccordance with the method disclosed in J. Biol. Chem., vol. 268, p.18415 (1993), the cells were cultured for 24 hours and then taken offfrom the plate, and the cells were dissolved. After centrifugalseparation for 5 minutes under 12000 g, the supernatant was used as acell extract. The cell extract was subjected to SDS polyacrylamide gelelectrophoresis to separate farnesyl-modified Ras protein andnon-farnesyl-modified Ras protein. The protein on the gel wastransferred onto a nitrocellulose membrane, and an anti-Ras proteinantibody was reacted as a probe (primary antibody reaction). Ananti-primary antibody, a peroxidase inclusion (secondary antibody), wasreacted, and then Ras protein was detected by a chemical fluorescenceenhancing kit. The proportion of non-farnesyl-modified Ras protein wasquantified by a densitometer and taken as the inhibitory activity.

The 50% inhibitory concentrations (IC₅₀ values) of the compounds of thepresent invention against farnesyl-modification of Ras protein are shownin Table 2.

                  TABLE 2    ______________________________________    50% inhibitory concentrations    against farnesyl-modification of Ras    protein           Compound                   IC.sub.50 (nM)    ______________________________________           Example 25                   21           Example 29                   4.7           Example 30                   21    ______________________________________

From the forgoing results, the compounds of the present invention haveexcellent inhibitory activities against protein-farnesyl transferase(PFT) and thus useful as antitumor agents, for example, against coloncancers, pancreatic cancers, myloid leukemias, lung cancer, carcinomacutaneum or thyroid gland cancer, particularly against pancreaticcancers.

The compound of the formula (I) of the present invention can be orallyor parenterally administered, and it may be formulated into aformulation suitable for such administration, so that it can be used asan antitumor agent. To use the compound of the present invention forclinical purpose, it may be formulated into various formulations by anaddition of pharmaceutically acceptable additives to meet the type ofadministration and then administered. As such additives, variousadditives which are commonly used in the field of drug formulations, maybe used, including, for example, gelatin, lactose, saccharose, titaniumoxide, starch, crystalline cellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, corn starch, microcrystalline wax, whitepetrolatum, magnesium metasilicate aluminate, anhydrous calciumphosphate, citric acid, trisodium citrate, hydroxypropylcellulose,sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acidester, polyoxyethylene hardened castor oil, polyvinylpyrrolidone,magnesium stearate, light silicic anhydride, talc, vegetable oil, benzylalcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrinand hydroxypropylcyclodextrin, etc.

A drug formulation to be prepared as a mixture with such additives, may,for example, be a solid formulation such as a tablet, a capsule, agranule, a powder or a suppository; or a liquid formulation such as asyrup, an elixir or an injection drug. These formulations can beprepared in accordance with conventional methods commonly employed inthe field of drug formulations. Further, in the case of a liquidformulation, it may be of the type which is to be dissolved or suspendedin water or in other suitable medium at the time of its use.Particularly, in the case of an injection drug, it may be dissolved orsuspended in a physiological saline or in a glucose solution, and abuffering agent or a preserving agent may further be added.

These formulations may contain the compound of the present invention ina proportion of from 1.0 to 100 wt %, preferably from 1.0 to 60 wt % ofthe total amount.

These formulations may further contain therapeutically effective othercompounds.

When the compound of the present invention is used as an antitumoragent, its dose and the frequency of administration vary depending uponthe sex, the age, the body weight and the diseased degree of the patientand the type and the range of the intended treating effects. However, inthe case of an oral administration, it is preferred to administer from0.01 to 20 mg/kg per day for an adult all at once or in a few times in adivided fashion. In the case of parenteral administration, it ispreferred to administer from 0.002 to 10 mg/kg per day for an adult allat once or in a few times in a divided fashion.

EXAMPLES AND REFERENCE EXAMPLES

Now, the present invention will be described in further detail withreference Examples and Reference Examples. However, the presentinvention is by no means restricted by such Examples.

Example 1 Preparation of N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid (1) Preparation of di-tert-butylN-{(1RS,2RS)-3-(5-ethoxycarbonyl-2-furyl)-1-methyl-2-(4-nitrophenyl)propyl)-N-(2-naphthylmethyl)carbamoylmethylsuccinate

1.15 g of ethyl5-{(2RS,3RS)-3-(2-naphthylmethylamino)-2-(4-nitrophenyl)butyl)-2-furancarboxylateobtained in Reference Example 1, 0.30 9 of 4-dimethylaminopyridine and0.91 g of 1,2-di-tert-butyl 1,2,3-propanetricarboxylate obtained inReference Example 2 were dissolved in 10 ml of methylene chloride, and0.93 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloridewas added thereto under cooling with ice with stirring, followed bystirring at room temperature for 18 hours. The reaction solution wasdiluted with ethyl acetate, and then, the organic layer was sequentiallywashed with 1N hydrochloric acid, a saturated sodium hydrogencarbonateaqueous solution and a saturated sodium chloride aqueous solution anddried over anhydrous magnesium sulfate. The drying agent was filteredoff, and then, the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=7/1+5/1) to obtain 1.44 g (yield: 80%) of the above-identifiedcompound as a slightly yellow oily substance.

(2) Preparation of di-tert-butylN-{(1RS,2RS)-3-(5-carboxy-2-furyl)-1-methyl-2-(4-nitrophenyl)propyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinate

1.44 g of di-tert-butyl N-(1RS,2RS)-3-(5-ethoxycarbonyl-2-furyl)-1-methyl-2-(4-nitrophenyl)propyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinatewas dissolved in a mixed solution of 15 ml of methanol and 7 ml oftetrahydrofuran, and 6 ml of a 1N sodium hydroxide aqueous solution wasadded thereto, followed by stirring at 40° C. for 2 hours. The reactionsolution was acidified by an addition of 2N hydrochloric acid and thenextracted with ethyl acetate. The organic layer was washed with asaturated sodium chloride aqueous solution and then dried over anhydrousmagnesium sulfate. The drying agent was filtered off, and then, thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (methylenechloride/methanol=100/1+50/1) to obtain 1.11 g (yield: 80%) of theabove-identified compound as a slightly yellow oily substance.

(3) Preparation of N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

50 mg of di-tert-butylN-{(1RS,2RS)-3-(5-carboxy-2-furyl)-1-methyl-2-(4-nitrophenyl)propyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinatewas dissolved in 10 ml of methylene chloride, and 11 mg of4-dimethylaminopyridine, 8 mg of aniline and 17 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedthereto, followed by stirring at room temperature for 18 hours. Thereaction solution was diluted with ethyl acetate, and then, sequentiallywashed with 1N hydrochloric acid, a saturated sodium hydrogencarbonateaqueous solution and a saturated sodium chloride aqueous solution anddried over anhydrous magnesium sulfate. The drying agent was filteredoff, and then, the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=5/1+3/1) to obtain 55 mg (yield: quantitative) of thedi-tert-butyl ester of the above-identified compound.

The ester thus obtained was dissolved in 2 ml of formic acid, followedby stirring at room temperature for 3 hours. Then, the reaction solutionwas evaporated to dryness under reduced pressure. Toluene was added tothe residue, and the mixture was again evaporated to dryness underreduced pressure. The obtained residue was treated with methylenechloride/hexane to obtain 36 mg (yield; 76%) of the above-identifiedcompound as a white crystalline powder.

¹ H-NMR(CDCl₃ +CD₃ OD)δ:0.94-1.02(3H, m), 2.50-3.50(8H, m),4.40-4.70(1H, m), 4.75-4.95(2H, m), 5.54 and 5.76(total 1H, each d, eachJ=3.4Hz), 6.81 and 6.95(total 1H, each d, each J=3.4Hz), 7.15(1H, t,J=7.2Hz), 7.30-7.60, 7.70-7.90 and 8.10-8.21(total 15H, each m)

FAB-MS;678(M+H)

Compounds of Examples 2 to 14 were prepared in the same manner as inExample 1 except that instead of ethyl5-{(2RS,3RS)-3-(2-naphthylmethylamino)-2-(4-nitrophenyl)butyl)-2-furancarboxylateand/or aniline used as the starting material in the above reaction, thecorresponding ester derivatives and/or amine compounds were employed.

Example 2 N-(1RS,2RS)-3-(5-(3,4-dimethoxyphenylcarbamoyl)-2-furyl}-1-methyl-2-(4-nitrophenyl)propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CDCl₃ +CD₃ OD)δ:0.95-1.02(3H, m), 2.60-3.60(8H, m),3.87-3.92(6H, m), 4.50-5.00(3H, m), 5.56-5.60 and 5.74-5.79(total 1H,each m), 6.80-7.00, 7.11-7.18 and 7.30-8.20(total 15H, each m)

FAB-MS:738(M+H)

Example 3 N-(1RS,2RS)-3-{5-(2-hydroxyphenylcarbamoyl)-2-furyl}-1-methyl-2-(4-nitrophenyl)propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CD₃ COCD₃)δ:0.80-1.10(3H, m), 2.60-4.00(8H, m), 4.60-5.10(3H,m), 5.72, 5.78 and 6.05(total 1H, each d, each J=3.2Hz), 6.80-7.10,7.35-7.65, 7.70-8.20(total 16H, each m)8.70-8.80 and 9.05-9.15(total 1H,each m)

FAB-MS:694(M+H)

Example 4 N-(1RS,2RS)-1-methyl-3-{5-(N-methylphenylcarbamoyl)-2-furyl)-2-(4-nitrophenyl)propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CD₃ COCD₃)δ:0.80-1.00(3H, m), 2.50-3.70(8H, m), 3.52 and3.55(total 3H, each s), 4.30-5.10(3H, m), 5.50-5.55, 5.60-5.65 and5.75-5.80(total 1H, each m), 7.10-7.30, 7.40-7.60, 7.75-8.00 and8.10-8.20(total 17H, each m)

FAB-MS:692(M+H)

Example 5 N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(3-pyridylcarbamoyl)-2-furyl}propyl)-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid hydrochloride

¹ H-NMR(CD₃ OD)δ:0.97-1.02(3H, m), 2.50-3.85(8H, m), 4.15-5.05(3H, m),5.79, 5.88 and 5.95(total 1H, each d, each J=3.5Hz), 6.99, 7.04 and7.11(total 1H, each d, each J=3.5Hz), 7.30-8.20(12H, m), 8.50-8.70,8.80-8.90 and 9.40-9.55(total 3H, each m)

FAB-MS:716(M+H)

Example 6 N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(4-pyridylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid hydrochloride

¹ H-NMR(CD₃ OD)δ:0.96-1.03(3H, m), 2.50-3.75(8H, m), 4.20-5.05(3H, m),5.77, 5.86 and 5.98(total 1H, each d, each J=3.5Hz), 7.05, 7.12 and7.20(total 1H, each d, each J=3.5Hz), 7.30-7.90, 8.08-8.18 and8.45-8.64(total 15H, each m)

FAB-MS:716(M+H)

Example 7 N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(5-pyrimidinylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid hydrochloride

¹ H-NMR(CD₃ OD)δ:0.97-1.03(3H, m), 2.55-3.75(8H, m), 4.50-5.00(3H, m),6.08(1H, d, J=3.8Hz), 7.10-7.60, 7.75-7.90 and 8.10-8.20(total 12H, eachm), 8.58-8.65, 8.80-8.90 and 9.18-9.22(total 3H, each m)

FAB-MS:717(M+H)

Example 8 N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(2-thiazolylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid hydrochloride

¹ H-NMR(CD₃ OD)δ:0.97-1.03(3H, m), 2.50-3.90(8H, m), 4.50-5.00(3H, m),5.80-6.10(1H, m), 7.07-8.16(14H, m)

FAB-MS:722(M+H)

Example 9 N-(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CDCl₃)δ:0.87 and 0.89(total 3H, each d, each J=6.8Hz),2.17-3.58(9H, m), 4.45-4.80(2H, m), 5.79(1H, d, J=3.3Hz), 6.94(1H, d,J=3.3Hz), 7.00-7.12, 7.28-7.39, 7.45-7.54 and 7.59-7.84(total 16H, eachm)

FAB-MS:667(M+H)

Example 10 N-(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(3-phenylcarbamoylphenyl)propyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CDCl₃)δ:0.80-1.05(3H, m), 2.30-3.50(8H, m), 4.20-5.40(3H, m),6.70-8.40(21H, m)

FAB-MS:677(M+H)

Example 11 N-(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-{3-(phenylcarbamoyl)-5-isoxazolyl)propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CD₃ OD)δ:0.83-1.01(3H, m), 2.42-3.43(8H, m), 3.52-3.64(1H, m),4.49-4.98(2H, m), 6.17 and 6.19(total 1H, each s), 7.11-7.35, 7.44-7.64and 7.74-7.89(total 14H, each m)

FAB-MS:668(M+H)

Example 12 N-(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(4-(phenylcarbamoyl)-2-pyridyl)propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CD₃ OD)δ:0.88-0.97(3H, m), 2.53-2.88(4H, m), 3.02-3.44(3H, m),3.54-3.79(1H, m), 4.49-4.53(1H, m), 4.72-5.03(2H, m), 7.11-7.27,7.34-7.55 and 7.65-7.89(total 18H, each m), 8.45-8.50(1H, m)

FAB-MS:678(M+H)

Example 13 (2R*)-2-N-(2-benzo b!thienylmethyl)-N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!carbamoylmethyl!succinicacid

¹ H-NMR(CD₃ OD)δ:1.04-1.11(3H, m), 2.55-3.45(8H, m), 4.24-4.37 and4.71-5.06(total 3H, each m), 5.67 and 5.69(total 1H, each d, eachJ=3.2Hz), 5.86-5.90(3H, m), 6.64-6.96(4H, m), 7.10-7.37 and7.59-7.81(total 10H, each m)

FAB-MS:683(M+H)

Example 14 (2R*)-2- N-(2-benzo b!thienylmethyl)-N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-(5-(3-pyridylcarbamoyl)-2-furyl}propyl)carbamoylmethyl!succinicacid hydrochloride

¹ H-NMR(CD₃ OD)δ:1.04-1.13(3H, m), 2.50-3.75(8H, m), 4.70-5.10(3H, m),5.86 and 5.90(total 2H, each s), 5.90-6.00(1H, m), 6.56-6.92(3H, m),7.04-7.40, 7.57-7.82 and 8.00-8.08(total 7H, each m), 8.54-8.57,8.67-8.70, 8.85-8.92, 9.44-9.45 and 9.53-9.57(total 3H, each m)

Example 15 Preparation of monopivaloyloxymethyl (2R*)-2- N-(2-benzob!thienylmethyl)-N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!carbamoylmethyl!succinate

38 mg of (2R*)-2- N-(2-benzo b!thienylmethyl)-N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-5-(phenylcarbamoyl)-2-furyl)propylcarbamoylmethyl!succinic acid(compound of Example 13) was dissolved in 2 ml of dimethylformamide, and23 μl of triethylamine and 16 μl of pivaloyloxymethyl chloride wereadded thereto, followed by stirring at 40° C. for 7 hours. The reactionsolution was poured into 0.1N hydrochloric acid and extracted with ethylether. Then, the organic layer was washed with a saturated sodiumchloride aqueous solution and dried over anhydrous magnesium sulfate.The drying agent was filtered off, and then, the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/3) to obtain 19 mg (yield:43%) of the above-identified compound

¹ H-NMR(CDCl₃)δ:1.05-1.13(3H, m), 2.49-3.33(8H, m), 3.97-4.94(3H, m),5.50-5.94(5H, m), 6.54-6.85(1H, m), 6.98-7.00(4H, m), 7.09-7.40(1H, m),7.53-7.81(10H, m)

FAB-MS:797(M+H)

Compounds of Examples 16 and 17 were prepared in the same manner as inExample 1 except that instead of ethyl5-{(2RS,3RS)-3-(2-naphthylmethylamino)-2-(4-nitrophenyl)butyl}-2-furancarboxylateused as the starting material in Example 1, the corresponding aminederivatives were employed.

Example 16 (2R*)-2-N-{(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(3-phenoxymethylphenyl)propyl}-N-(2-naphthylmethyl)carbamoylmethyl!succinicacid

¹ H-NMR(CDCl₃)δ:0.85-1.00(3H, m), 2.48-3.55(8H, m), 3.87(3H, s),4.22-4.80(3H, m), 4.83-4.88(2H, m), 5.10-5.50(1H, br), 6.22-6.35,6.72-7.20, 7.20-7.31 and 7.35-7.90(total 19H, each m)

FAB-MS:688(M+H)

Example 17 (2R*)-2- N-(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{3-(phenoxymethyl)-5-(1,2,4-oxadiazolyl)}-propyl!-N-(2-naphthylmethyl)carbamoylmethyl!succinicacid

¹ H-NMR(CD₃ COCD₃)δ:0.92-1.01(3H, m), 2.61-3.80(9H, m), 3.85(3H, s),4.60-5.10(2H, m), 5.20-5.35(2H, m), 7.28-7.60(7H, m), 7.77-7.96(6H, m)

FAB-MS:680(M+H)

Example 18 (2R*)-2- N-(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{(E)-3-styrylphenyl}propyl!-N-(2-naphthylmethyl)carbamoylmethyl!succinicacid

¹ H-NMR(CDCl₃)δ:0.82-0.95(3H, m), 2.40-3.80(9H, m), 3.86-3.88(3H, m),4.20-4.90(2H, m), 6.15-6.98(6H, m), 7.02-7.67(11H, m), 7.72-7.95(5H, m)

FAB-MS:684(M+H)

Example 19 (2R*)-2- N-(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(3-(2-phenylethyl)phenyl!propyl!-N-(2-naphthylmethyl)carbamoylmethyl!succinicacid

183 mg of di-tert-butyl (2R* )-2- N-(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{(E)-3-styrylphenyl)propyl!-N-(2-naphthylmethyl)carbamoylmethyl!succinateas a diester of the compound of Example 18, was dissolved in 5 ml ofmethanol, and 20 mg of a 10% palladium-carbon catalyst was addedthereto, followed by catalytic reduction at room temperature underatmospheric pressure with hydrogen overnight. The reaction solution wasfiltered through a cerite filter, and the filtrate was concentratedunder reduced pressure. Then, the residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/1) to obtain 125 mg(yield: 68%) of a di-tert-butyl ester of the above-identified compound.

120 mg of the ester thus obtained was dissolved in 4 ml oftrifluoroacetic acid, followed by stirring at room temperature for onehour. Then, trifluoroacetic acid was distilled off under reducedpressure. The residue was purified by medium pressure liquidchromatography (Lobor column™, size A, RP-8 (manufactured by Merck Co.);acetonitrile/0.1% trifluoroacetic acid aqueous solution=2/1) to obtain89 mg (yield: 87%) of the above-identified compound as a colorless foam.

¹ H-NMR(CDCl₃)δ:0.82-1.00(3H, m), 2.50-3.18(12H, m), 3.33-3.57(1H, m),3.84(3H, s), 4.25-4.90(2H, m), 6.08-6.97, 7.02-7.50 and 7.58-7.92(total20H, each m)

FAB-MS:686(M+H)

Example 20N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)propyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

22 mg ofN-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)propyl)-2-naphthylmethylamineobtained in Reference Example 3 was dissolved in 1 ml of methylenechloride, and 12 mg of chloroformylmethylsuccinic anhydride and 12 μl ofdiisopropylethylamine were added thereto, followed by stirring at roomtemperature for 45 minutes. The reaction solution was evaporated todryness under reduced pressure. Then, the residue was dissolved in amixed solution of 1 ml of tetrahydrofuran and 0.5 ml of water, and 40 mgof lithium hydroxide monohydrate was added thereto, followed by stirringat room temperature for 15 minutes. The reaction solution was dilutedwith ethyl ether, then acidified by an addition of 1N hydrochloric acid,washed with a saturated sodium chloride aqueous solution and then driedover anhydrous magnesium sulfate. The drying agent was filtered off, andthen, the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column thin layer chromatography(Kieselgel™60F₂₅₄, Art™5744; chloroform/methanol=7/1) to obtain 15 mg(yield: 53%) of the above-identified compound as a colorless oilysubstance.

¹ H-NMR(CDCl₃ +CD₃ OD)δ:0.80-1.05(3H, m), 2.45-3.50(8H, m), 4.25-4.40,5.10-5.45(total 1H, m), 4.45-4.83(2H, m), 6.18-7.90(20H, m)

FAB-MS:658(M+H)

Compounds of Examples 21 to 22 were prepared in the same manner as inExample 20 except that instead ofN-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)propyl)-2-naphthylmethylamineused as the starting material in the above reaction, the correspondingamine derivatives were employed.

Example 21 N-(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-{(E)-3-styrylphenyl)propyl!-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CDCl₃ +CD₃ OD)δ:0.86-1.00(3H, m), 2.48-3.45(8H, m),4.30-4.95(3H, m), 6.31-7.90(22H, m)

FAB-MS:660(M+H)

Example 22 N-(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(5-phenoxymethyl-2-furyl)propyl}-N-(2-naphthylmethyl)carbamoylmethylsuccinicacid

¹ H-NMR(CD₃ COCD₃)δ:0.85-1.01(3H, m), 2.50-3.70(9H, m), 3.85(3H, s),4.50-5.02(4H, m), 5.45-5.55 and 5.70-5.75(total 1H, each m), 6.05-6.10and 6.18-6.22(total 1H, each m), 6.90-7.01(3H, m), 7.10-7.60(7H, m),7.78-7.95(6H, m)

FAB-MS:678(M+H)

Example 23 Preparation of 4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-1,2,3-butanetricarboxylicacid (1) Preparation of N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl)propyl!-2-naphthylmethylamine

1.15 g of ethyl5-{(2RS,3RS)-3-(2-naphthylmethylamino)-2-(4-nitrophenyl)butyl)-2-furancarboxylateobtained in Reference Example 1, was dissolved in 10 ml of ethanol, and4 ml of a 1N sodium hydroxide aqueous solution was added thereto,followed by stirring at 40° C. for 2.5 hours. The solvent was distilledoff under reduced pressure, and the residue was acidified by an additionof 1N hydrochloric acid and then extracted by an addition of ethylacetate. The organic layer was washed with a saturated sodium chlorideaqueous solution and then dried over anhydrous magnesium sulfate. Thedrying agent was filtered off, and then, the solvent was distilled offunder reduced pressure. The residue was dissolved in 5 ml ofdimethylformamide. Then, 453 mg of aniline was added thereto, and then587 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloridewas added thereto, followed by stirring at room temperature overnight.The reaction solution was diluted with ethyl acetate, sequentiallywashed with 1N hydrochloric acid, water, a 1N sodium hydroxide aqueoussolution and a saturated sodium chloride aqueous solution and dried overanhydrous magnesium sulfate. Then, the drying agent was filtered off.The solvent was distilled off under reduced pressure. Then, the residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/1+1/1) to obtain 973 mg (yield: 77%) of the above-identifiedcompound as a slightly yellow foam.

(2) Preparation of 4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-1,2,3-butanetricarboxylicacid

21 mg of 2,3,4-triethyl 1,2,3,4-butanetetracarboxylate (the one obtainedby dissolving a commercially available tetraethyl ester ofmeso-butane-1,2,3,4-tetracarboxylic acid in ethanol and partiallyhydrolyzing the ester by an addition of 1 equivalent, based on theester, of a 1N sodium hydroxide aqueous solution) was dissolved in 2 mlof chloroform, and 5 μl of thionyl chloride was added thereto, followedby heating and refluxing for one hour. The reaction solution was cooledto 0° C., and then 0.5 ml of a chloroform solution containing 35 mg ofN-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl)-2-naphthylmethylamine,was added thereto, followed by stirring at room temperature for 2 hours.A saturated sodium hydrogencarbonate aqueous solution was added to thereaction solution, and the mixture was extracted with ethyl acetate.Then, the organic layer was washed with a saturated sodium chlorideaqueous solution and dried over anhydrous magnesium sulfate. The dryingagent was filtered off, and then, the solvent was distilled off underreduced pressure. The residue was purified by silica gel thin layerchromatography (Kieselgel™60F₂₅₄₁ Art™5744; hexane/ethyl acetate=1/1) toobtain 24 mg (yield: 43%) of a triethyl ester of the above-identifiedcompound.

The ester thus obtained was dissolved in a mixed solution of 2 ml oftetrahydrofuran and 2 ml of ethanol, and 1 ml of a 3N sodium hydroxideaqueous solution was added thereto, followed by stirring at roomtemperature for 18 hours. The mixture was acidified by an addition of 1Nhydrochloric acid and then extracted with ethyl acetate. The organiclayer was washed with a saturated sodium chloride aqueous solution andthen dried over anhydrous magnesium sulfate. The drying agent wasfiltered off, and then, the solvent was distilled off under reducedpressure. The residue was purified by medium pressure liquidchromatography (Lobor column™, size A, RP-8 (manufactured by Merck Co.);acetonitrile/0.1% trifluoroacetic acid aqueous solution=1/1) to obtain15 mg (yield: 70%) of the above-identified compound as a white powder.

¹ H-NMR(CD₃ COCD₃)δ:0.80-1.10(3H, m), 2.30-3.90(9H, m), 4.60-5.20(3H,m), 5.70-6.70(1H, m), 6.80-7.00(1H, m), 7.10-8.30(16H, m), 8.80-9.00 and9.20-9.40(total 1H, m)

FAB-MS:736(M+H)

Example 24 Preparation of disodium (3RS,4RS)-3-carboxylato-4-hydroxy-4-N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!butanoateand disodium (3SR,4SR)-3-carboxylato-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!butanoate(1) Preparation of tert-butyl (2RS,3RS)-2- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!-5-oxotetrahydrofuran-3-carboxylateand tert-butyl (2SR,3SR)-2- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl)-5-oxotetrahydrofuran-3-carboxylate

87 mg of N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl)propyl!-2-naphthylmethylamineobtained in Example 23(1), 54 mg of(2RS,3RS)-3-tert-butoxycarbonyl-5-oxotetrahydrofuran-2-carboxylic acidprepared by the method of Reference Example 4 and 97 μl of triethylaminewere dissolved in 3 ml of chloroform, and 1 ml of a chloroform solutioncontaining 59 mg of 2-chloro-1,3-dimethylimidazolium chloride undercooling with ice, followed by stirring at the same temperature for 30minutes. The reaction solution was poured into water and extracted withchloroform. The extract solution was dried over anhydrous magnesiumsulfate. The drying agent was filtered off, and then, the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=2/1), whereby theabove-identified compounds which are in the relation of diastereomers,were obtained as colorless oily substances in amounts of 39 mg (thecomponent eluting first in the silica gel column chromatography: yield:32%) and 49 mg (the component eluting later in the silica gel columnchromatography: yield: 40%), respectively.

(2) Preparation of (2RS,3RS)-2- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-5-oxotetrahydrofuran-3-carboxylicacid and (2SR,3SR)-2- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!-5-oxotetrahydrofuran-3-carboxylicacid

28 mg of tert-butyl (2RS,3RS)-2- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!-5-oxotetrahydrofuran-3-carboxylatewas dissolved in 1 ml of formic acid, and the solution was left to standat room temperature overnight. The reaction solution was distilled offunder reduced pressure. Then, toluene was added to the residue, followedby redistillation to obtain 26 mg (yield: 99%) of the above-identifiedcompound as a white foam.

¹ H-NMR(CDCl₃)δ:0.80-1.05(3H, m), 2.40-3.70(6H, m), 4.00-4.20, 4.40-4.60and 4.80-5.30(total 4H, each m), 5.50-5.85(1H, m), 6.70-7.00(1H, m),7.05-7.85 and 8.10-8.50(total 17H, m)

FAB-MS:676(M+H)

A similar reaction was carried out to obtain a compound which is in arelation of a diastereomer.

(2SR,3SR)-2- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!-5-oxotetrahydrofuran-3-carboxylicacid

¹ H-NMR(CDCl₃)δ:0.95 and 1.05(total 3H, each d, J=6.7Hz), 2.70-4.90(7H,m), 5.00-5.80(4H, m), 6.75-6.95(1H, m), 7.05-8.30 and 8.50-8.80(total17H, m)

FAB-MS:676 (M+H)

(3) Preparation of disodium (3RS,4RS)-3-carboxylato-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!butanoateand disodium (3SR,4SR)-3-carboxylato-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!butanoate

26 mg of (3RS,4RS)-5- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!-2-oxotetrahydrofuran-4-carboxylicacid was dissolved in 5 ml of methanol, and 76 μl of a 1N sodiumhydroxide aqueous solution was added thereto, followed by stirring atroom temperature for 30 minutes. The reaction solution was evaporated todryness under reduced pressure to obtain 28 mg (yield: quantitative) ofthe above-identified compound as a white solid.

¹ H-NMR(CD₃ OD)δ:0.80-1.05(3H, m), 2.40-3.70(6H, m), 4.70-5.20(4H, m),5.60-5.80(1H, m), 6.70-6.85(1H, m), 7.15-8.20(16H, m)

FAB-MS:716(M+Na)

A similar reaction was carried out to obtain a compound which is in arelation of a diastereomer.

Disodium (3SR,4SR)-3-carboxylato-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!butanoate

¹ H-NMR(CD₃ OD)δ:0.80-1.10(3H, m), 2.55-3.70(6H, m), 4.60-4.95 and5.15-5.50(4H, each m), 5.62 and 5.71(total 1H, each d, each J=3.1Hz),7.05-7.15 and 7.30-8.20(total 16H, each m)

FAB-MS:716(M+Na)

Example 25 Preparation of 3-tert-butoxycarbonyl-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!-3-butenoicacid (1) Preparation of methyl 3-tert-butoxycarbonyl-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!butanoate

49 mg of tert-butyl (2RS,3RS)-2-(N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!-5-oxotetrahydrofuran-3-carboxylateobtained in Example 24(1) was dissolved in a mixed solution of 2 ml oftetrahydrofuran and 0.5 ml of water, and a 1N sodium hydroxide aqueoussolution was added thereto, followed by stirring at room temperature for15 hours. The reaction solution was acidified by an addition of 1Nhydrochloric acid and then extracted with ethyl acetate. The extractsolution was dried over anhydrous magnesium sulfate. The drying agentwas filtered off, and then, a small excess amount of diazomethane wasadded to the filtrate at room temperature. The solvent was distilled offunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=2/1) to obtain 202 mg(yield: 78%) of the above-identified compound as a yellow oilysubstance.

(2) Preparation of methyl 3-tert-butoxycarbonyl-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-3-butenoate

40 mg of methyl 3-tert-butoxycarbonyl-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!butanoatewas dissolved in 5 ml of chloroform, and 68 mg of Dess-Martin reagentwas added thereto, followed by stirring at room temperature for onehour. The reaction solution was poured into a mixed solution of asaturated sodium hydrogencarbonate aqueous solution and a saturatedsodium thiosulfate aqueous solution and extracted with ethyl acetate.The organic layer was washed with a saturated sodium chloride aqueoussolution and then dried over anhydrous magnesium sulfate. The dryingagent was filtered off, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel thin layerchromatography (Kieselgel™60F₂₅₄, Art™5744; hexane/ethyl acetate=3/2) toobtain 16 mg (yield: 40%) of the above-identified compound as acolorless oily substance.

(3) Preparation of 3-tert-butoxycarbonyl-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-3-butenoicacid

16 mg of methyl 3-tert-butoxycarbonyl-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-3-butenoatewas dissolved in a mixed solution of 1 ml of tetrahydrofuran and 0.3 mlof water, and 0.3 ml of a 1N sodium hydroxide aqueous solution was addedthereto, followed by stirring at room temperature for 2 days. Thereaction solution was acidified by an addition of 1N hydrochloric acidand then extracted with ethyl acetate. The extract solution was driedover anhydrous magnesium sulfate. The drying agent was filtered off, andthen, the solvent was distilled off under reduced pressure. The residuewas purified by silica gel thin layer chromatography (Kieselgel™60F₂₅₄,Art™5744; chloroform/methanol=8/1) to obtain 7.7 mg (yield: 49%) of theabove-identified compound as a colorless foam.

¹ H-NMR(CDCl₃)δ:0.80-1.10(3H, m), 1.40-1.50(9H, m), 2.80-3.40(5H, m),4.40-5.10(4H, m), 5.45-5.73(1H, m), 6.70-7.00(1H, m), 7.00-8.20(17H, m)

FAB-MS:748(M+H)

Compounds of Examples 26 and 27 were prepared in the same manner as inExample 25 except that instead ofN-{(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl}-2-naphthylmethylamine,the corresponding amine derivatives were employed.

Example 26 3-tert-butoxycarbonyl-4-hydroxy-4-(N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl)propyl!-N-(2-naphthylmethyl)carbamoyl!-3-butenoicacid

¹ H-NMR(CDCl₃)δ:0.80-1.10(3H, m), 1.35-1.55(9H, m), 2.30-3.20(5H, m),4.25-5.00(4H, m), 5.30-5.90(3H, m), 6.30-6.95(4H, m), 7.05-7.15 and7.30-7.90(total 13H, each m)

FAB-MS;747(M+H)

Example 27 3-tert-butoxycarbonyl-4-hydroxy-4-N-{(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(3-phenoxymethylphenyl)propyl}-N-(2-naphthylmethyl)carbamoyl!-3-butenoicacid

¹ H-NMR(CDCl₃)δ:0.82-1.10(3H, m), 1.39-1.58(9H, m), 2.29-3.32(5H, m),4.38-5.02(6H, m), 6.12-8.02(20H, m)

FAB-MS:745(M+H)

Example 28 Preparation of 4-hydroxy-3-methoxycarbonyl-4- N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-3-butenoicacid

89 mg of disodium (3RS,4RS)-4-(N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-3-carboxylato-4-hydroxybutanoateobtained in the same manner as in Example 24 except that instead ofN-{(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl}-2-naphthylmethylamineused as the starting material in Example 24,N-{(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl}-2-naphthylmethylaminewas employed, was dissolved in water. The solution was acidified by anaddition of 1N hydrochloric acid and extracted with ethyl acetate. Theextract solution was dried over anhydrous magnesium sulfate. The dryingagent was filtered off, and then, the solvent was distilled off underreduced pressure. The residue was dissolved in 2 ml of ethyl acetate,and a small excess amount of diazomethane was added thereto. Then, thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=2/1+1/1), and the obtained dimethyl ester was treated in thesame manner as in Example 25(2) and (3) to obtain 13 mg (yield: 15%) ofthe above-identified compound as a colorless oily substance.

¹ H-NMR(CDCl₃)δ:0.95-1.15(3H, m), 2.80-3.30(5H, m), 3.65-3.90(3H, m),4.20-4.90(4H, m), 5.45-5.55 and 5.65-5.95(total 3H, each m),6.35-7.00(4H, m), 7.05-7.15 and 7.25-7.90(13H, each m)

FAB-MS:705(M+H)

Example 29 Preparation of 3-allyloxycarbonyl-4-hydroxy-4- N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-3-butenoicacid

80 mg of disodium (3RS,4RS)-4- N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-3-carboxylato-4-hydroxybutanoateas the starting material of Example 28, was dissolved in 2 ml ofdimethylformamide, and 37 μl of allyl bromide was added thereto,followed by stirring at room temperature for 3 days. The reactionsolution was poured into water and extracted with ethyl ether and thendried over anhydrous magnesium sulfate. The drying agent was filteredoff, and then, the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/2), and the obtained diallyl ester was treated in the samemanner as in Example 25(2) and (3) to obtain 4.4 mg (yield: 2.4%) of theabove-identified compound as a colorless oily substance.

¹ H-NMR(CDCl₃)δ:0.80-1.10(3H, m), 2.50-3.30(5H, m), 4.20-4.95(6H, m),5.20-5.55(2H, m), 5.70-6.00(3H, m), 6.35-7.00(5H, m), 7.05-7.15 and7.25-8.00(13H, m)

FAB-MS:731(M+H)

Example 30 Preparation of 5-hydroxy-4-isopropoxycarbonyl-5- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-4-pentenoicacid (1) Preparation of isopropyl 5-hydroxy-4-isopropoxycarbonyl-5- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!pentanoate

99 mg of isopropyl 5-acetoxy-4-isopropoxycarbonyl-5- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!pentanoateobtained by subjectingN-{(1RS,2RS)-1-methyl-2-(4-nitrophenyl)3-{5-(phenylcarbamoyl)-2-furyl}propyl!-2-naphthylmethylamineobtained in Example 23(1) and 2,4-diisopropyl1-acetoxy-1,2,4-butanetricarboxylate obtained in Reference Example 5 toa condensation reaction in accordance with the method of Example 24(1),was dissolved in 3 ml of isopropanol, and 9.8 mg of sodium isopropoxidewas added thereto, followed by stirring at room temperature for onehour. The reaction solution was poured into water and extracted withethyl acetate. Then, the organic layer was dried over anhydrousmagnesium sulfate. The drying agent was filtered off, and then, thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=2/1)to obtain 43 mg (yield: 45%) of the above-identified compound.

(2) Preparation of 5-hydroxy-4-isopropoxycarbonyl-5- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!-4-pentenoicacid

Isopropyl 5-hydroxy-4-isopropoxycarbonyl-5- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2-naphthylmethyl)carbamoyl!pentanoatewas treated in the same manner as in Example 25(2) and (3) to obtain theabove-identified compound as a colorless oily substance.

¹ H-NMR(CDCl₃)δ:0.82-1.00(3H, m), 1.17-1.35(6H, m), 2.10-3.80(7H, m),4.10-5.16(5H, m), 5.49-5.73(1H, m), 6.78-6.94(1H, m), 7.06-8.22(17H, m)

FAB-MS:748(M+H)

Example 31 Preparation of 3-tert-butoxycarbonyl-4-N-(2,3-dichlorobenzyl)-N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!carbamoyl!-4-hydroxy-3-butenoicacid

Tert-butyl (3RS,4RS)-5- N-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-N-(2,3-dichlorobenzyl)carbamoyl!-2-oxotetrahydrofuran-4-carboxylateobtained in the same manner as in Example 24(1) except that instead ofN-(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl!-2-naphthylmethylamineused as the starting material in Example 24, the corresponding aminederivative was used, was treated in the same manner as in Example 25(2)and (3) to obtain the above-identified compound as a colorless oilysubstance.

¹ H-NMR(CDCl₃)δ:0.80-1.10(3H, m), 1.20-1.50(9H, m), 2.75-3.20 and3.55-3.75(total 5H, m), 4.30-5.00(4H, m), 5.55-5.95(1H, m),6.90-7.00(1H, m), 7.00-7.70 and 8.10-8.20(total 13H, m)

FAB-MS:768(M+H)

Reference Example 1 Preparation of ethyl5-{(2RS,3RS)-3-(2-naphthylmethylamino)-2-(4-nitrophenyl)butyl}-2-furancarboxylate(1) Preparation of ethyl5-{2-(4-nitrophenyl)-3-oxobutyl}-2-furancarboxylate

3.00 g of p-nitrophenylacetone was dissolved in 50 ml ofdimethylformamide, and 0.70 g of 60% oily sodium hydride was added undercooling with ice with stirring, followed by stirring at the sametemperature for 10 minutes. 5 ml of a dimethylformamide solutioncontaining 3.40 g of ethyl 5-chloromethyl-2-furancarboxylate, and 3.05 gof potassium iodide were added thereto, followed by stirring at roomtemperature for 2.5 hours. Then, the reaction solution was acidified byan addition of acetic acid. Water and ethyl ether were added, and themixture was extracted. Then, the organic layer was washed with asaturated sodium chloride aqueous solution and dried over anhydrousmagnesium sulfate. The drying agent was filtered off, and then, thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=5/1+2/1) to obtain 5.48 g of the above-identified compound.

(2) Preparation of ethyl5-{(2RS,3SR)-3-hydroxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate

5.48 g of ethyl 5-(2-(4-nitrophenyl)-3-oxobutyl)-2-furancarboxylate wasdissolved in 50 ml of tetrahydrofuran, and 16.5 ml of a 1Mtetrahydrofuran solution of lithium tri-sec-butylborohydride was addedunder cooling to -78° C. with stirring, followed by stirring at the sametemperature for 2 hours. Water was added to the reaction solution,followed by stirring at room temperature for 30 minutes. Then, thesolution was acidified by an addition of acetic acid. Ethyl acetate wasadded thereto for extraction. The organic layer was washed with asaturated sodium chloride aqueous solution and then dried over anhydrousmagnesium sulfate. The drying agent was filtered off, and then, thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=5/1+1/1) to obtain 3.66 g of the above-identified compound.

(3) Preparation of ethyl5-{(2RS,3RS)-3-azido-2-(4-nitrophenyl)butyl}-2-furancarboxylate

3.66 g of ethyl5-{(2RS,3SR)-3-hydroxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate wasdissolved in 40 ml of tetrahydrofuran, and 4.32 g of triphenylphosphine,2.60 ml of diethyl azodicarboxylate and 4.53 g of diphenylphosphorylazide were added under cooling with ice with stirring, followed bystirring at room temperature for 18 hours. The reaction solution wasevaporated to dryness under reduced pressure. Then, the residue waspurified by silica gel column chromatography (hexane/ethyl acetate=50/1)to obtain 3.24 g of the above-identified compound.

(4) Preparation of ethyl5-{(2RS,3RS)-3-amino-2-(4-nitrophenyl)butyl}-2-furancarboxylate

3.24 g of ethyl5-{(2RS,3RS)-3-azido-2-(4-nitrophenyl)butyl}-2-furancarboxylate wasdissolved in a mixed solution of 50 ml of tetrahydrofuran and 5 ml ofwater, and 2.37 g of triphenylphosphine was added thereto, followed byheating and refluxing for 6 hours. The reaction solution was left tocool to room temperature, and then ethyl ether and water were addedthereto for extraction. The organic layer was washed with a saturatedsodium chloride aqueous solution and then dried over anhydrous magnesiumsulfate. The drying agent was filtered off, and then, the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (methylene chloride/methanol=100/1+20/1) toobtain 2.89 g of the above-identified compound.

(5) Preparation of ethyl5-{(2RS,3RS)-3-(2-naphthylmethylamino)-2-(4-nitrophenyl)butyl}-2-furancarboxylate

0.97 g of ethyl5-{(2RS,3RS)-3-amino-2-(4-nitrophenyl)butyl}-2-furancarboxylate wasdissolved in 10 ml of methanol, and 0.48 g of 2-naphthoaldehyde wasadded thereto, followed by heating under reflux for 1.5 hours. Thereaction solution was left to cool to room temperature. Then, 0.16 g ofsodium borohydride was added thereto, followed by stirring at roomtemperature for 15 minutes. Water and ethyl acetate were added to thereaction solution for extraction. The organic layer was washed with asaturated sodium chloride aqueous solution and then dried over anhydrousmagnesium sulfate. The drying agent was filtered off, and then, thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=4/1)to obtain 1.15 g of the above-identified compound.

The reactions were carried out in the same manner as in ReferenceExample 1 except that instead of p-nitrophenylacetone and/or ethyl5-chloromethyl-2-furancarboxylate and/or 2-naphthoaldehyde used as thestarting material in the above reaction, the corresponding arylacetonederivative and/or halide and/or arylaldehyde derivative was used, toobtain ethyl5-{(2RS,3RS)-2-(4-chlorophenyl)-3-(2-naphthylmethylamino)butyl}-2-furancarboxylate,ethyl3-{(2RS,3RS)-2-(4-chlorophenyl)-3-(2-naphthylmethylamino)butyl!benzoate,ethyl5-{(2RS,3RS)-2-(4-chlorophenyl)-3-(2-naphthylmethylamino)butyl}-3-isoxazolecarboxylate,ethyl2-{(2RS,3RS)-2-(4-chlorophenyl)-3-(2-naphthylmethylamino)butyl}-5-pyridinecarboxylate,ethyl 5-{(2RS,3RS)-3-(2-benzob!thienylmethylamino)-2-(3,4-methylenedioxyphenyl)butyl}-2-furancarboxylate,N-{1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(3-phenoxymethylphenyl)propyl}-2-naphthylmethylamine,N-(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{5-(phenoxymethyl)-3-(1,2,4-oxadiazolyl)}propyl!-2-naphthylmethylamine,N-{(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{(E)-3-styrylphenyl}propyl!-2-naphthylmethylamine,N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-{(E)-3-styrylphenyl}propyl!-2-naphthylmethylamine,N-{(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(5-phenoxymethyl-2-furyl)propyl}-2-naphthylmethylamineand ethyl5-{(2RS,3RS)-2-(4-nitrophenyl)-3-(2,3-dichlorobenzylamino)butyl}-2-furancarboxylate.

Reference Example 2 Preparation of 1,2-di-tert-butyl1,2,3-propanetricarboxylate and its optical resolution

13.1 ml of a 1.5M cyclohexane solution of lithium diisopropylamide wasdissolved in 10 ml of tetrahydrofuran, and a tetrahydrofuran solution(10 ml) containing 2.96 g of benzyl acetate was added under cooling to-70° C. with stirring, followed by stirring at the same temperature for30 minutes. Then, a tetrahydrofuran solution (10 ml) containing 2.96 gof di-tert-butyl maleate, was dropwise added thereto, followed bystirring at the same temperature for 30 minutes. The reaction solutionwas extracted by an addition of 20 ml of water and 50 ml of ethyl ether.The organic layer was separated, then washed with a saturated sodiumchloride aqueous solution and dried over anhydrous magnesium sulfate.Then, the solvent was distilled off under reduced pressure. The residuewas dissolved in 50 ml of dioxane, and 0.4 g of a 10% palladium carboncatalyst was added thereto, followed by catalytic reduction for 20 hoursat room temperature under hydrogen atmospheric pressure. The catalystwas filtered off, and then, the solvent was distilled off under reducedpressure. The residue was treated with hexane, whereupon the precipitatethereby obtained was collected by filtration and then dried to obtain3.02 g of the above-identified compound as colorless crystalline powder,mp 55-57° C.

12.97 g of the di-tert-butyl ester thus obtained and 13.24 g ofcinchonidine was dissolved under heating in le of carbon tetrachloride.Then, seed crystals were added thereto, and the mixture was left tostand at room temperature for 24 hours. The crystals were collected byfiltration and then again dissolved under heating in 1l of carbontetrachloride, and seed crystals were added thereto, and the mixture wasleft to stand for 24 hours. This operation was further repeated twice toobtain 6.66 g of a cinchonidine salt of the above-identified compound,which is named as the (S*)-isomer for the sake of convenience, α!_(D) ²⁰-62.7° (c 1.0, chloroform).

The cinchonidine salt thus obtained was dissolved in a mixed solution ofethyl ether and 1N hydrochloric acid under cooling with ice, and theorganic layer was separated and then post-treated in accordance with aconventional method to obtain the (S*)-isomer of the above-identifiedcompound as colorless oily substance, a!_(D) ²⁰ +4.44° (c 0.92,chloroform).

The fraction containing a large amount of the other mirror image isomerobtained in the above optical resolution operation, was converted to afree acid, and then, the same operation was carried out in isopropylether using quinine, whereby the mirror image isomer named as the(R*)-isomer for the sake of convenience, was obtained.

Reference Example 3 Preparation ofN-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)propyl}-2-naphthylmethylamine

1.54 g of (2RS,3SR)-4-(4-bromophenyl)-3-(4-chlorophenyl)-2-butanol(prepared in the same manner as in Reference Example 1) was dissolved in45 ml of dimethylformamide, and 1.4 g of tert-butyldimethylsilylchloride and 1.2 g of imidazole were added thereto, followed by stirringat room temperature for one hour. Ethyl ether and water were added tothe reaction solution for extraction. The organic layer was washed witha saturated sodium chloride aqueous solution and then dried overanhydrous magnesium sulfate. The drying agent was filtered off, andthen, the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=15/1) to obtain 2.02 g (yield: 99%) of(2RS,3SR)-4-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)-3-(4-chlorophenyl)butane.

200 mg of the silyl-protected compound thereby obtained was dissolved in10 ml of toluene, and 400 mg of tributyl(phenylethynyl)tin and 44 mg oftetrakis(triphenylphosphine)palladium were added thereto, followed byheating and refluxing for 5 hours. A potassium fluoride aqueous solutionand ethyl ether were added to the reaction solution and thoroughly mixedby shaking. Then, the organic layer was separated, washed with asaturated sodium chloride aqueous solution and then dried over anhydroussodium sulfate. The drying agent was filtered off, and then, the solventwas distilled off under reduced pressure. The residue was dissolved in 5ml of tetrahydrofuran, and 2 ml of a 1M tetrahydrofuran solution oftetrabutylammonium fluoride was added thereto, followed by stirring atroom temperature for 7 hours. A saturated ammonium chloride aqueoussolution and ethyl acetate were added to the reaction solution forextraction. The organic layer was washed with a saturated sodiumchloride aqueous solution and then dried over anhydrous magnesiumsulfate. The drying agent was filtered off, and then, the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=10/1) to obtain 141 mg(yield: 89%) of(2RS,3SR)-3-(4-chlorophenyl)-4-(4-phenylethynylphenyl)-2-butanol.

141 mg of the alcohol compound thus obtained was dissolved in 2 ml ofethyl acetate, and 62 μl of methanesulfonyl chloride and 161 μl oftriethylamine were added thereto, followed by stirring at roomtemperature for 30 minutes. Insoluble precipitates were filtered offfrom the reaction solution. Then, the filtrate was concentrated underreduced pressure, and the residue was dissolved in 5 ml ofdimethylformamide. Then, 255 mg of sodium azide was added thereto,followed by heating at 80° C. for 4 hours. The reaction solution wasleft to cool to room temperature. Then, ethyl ether and water were addedthereto for extraction. The organic layer was washed with a saturatedsodium chloride aqueous solution and then dried over anhydrous magnesiumsulfate. The drying agent was filtered off, and then, the solvent wasdistilled off under reduced pressure. The residue was heated andrefluxed together with 187 mg of triphenylphosphine in 7 ml of 10%-watercontaining tetrahydrofuran for one hour. The reaction solution wasevaporated to dryness under reduced pressure. Then, the residue wasdissolved in ethanol and again evaporated to dryness under reducedpressure. The obtained residue was purified by silica gel columnchromatography (chloroform/methanol=50/1+10/1) to obtain 129 mg (yield:92%) of(1RS,2SR)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)propylamine

38 mg of the amine compound thus obtained was dissolved in 1 ml ofmethanol, and 20 mg of 2-naphthoaldehyde was added thereto, followed byheating and refluxing for 6 hours. The reaction solution was left tocool to room temperature, and then, 5 mg of sodium borohydride was addedthereto, followed by stirring at room temperature for 30 minutes. Asaturated ammonium chloride aqueous solution and ethyl ether were addedto the reaction solution for extraction. The organic layer was washedwith a saturated sodium chloride aqueous solution and then dried overanhydrous magnesium sulfate. The drying agent was filtered off, andthen, the solvent was distilled off under reduced pressure. The residuewas purified by silica gel thin layer chromatography (hexane/ethylacetate=4/1) to obtain 22 mg (yield: 42%) of the above-identifiedcompound.

The reaction was carried out in the same manner as in Reference Example3 except that instead of tributyl(phenylethynyl)tin used as the startingmaterial in the above reaction, tributyl(styryl)tin was employed, toobtainN-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-(3-styrylphenyl)propyl}-2-naphthylmethylamine.

Reference Example 4 Preparation of(2RS,3RS)-3-tert-butoxycarbonyl-5-oxotetrahydrofuran-2-carboxylic acid(1) Preparation of(2RS,3SR)-2-benzyloxycarbonyl-5-oxotetrahydrofuran-3-carboxylic acid

5.3 g of (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylic acid wasdissolved in 90 ml of acetone, and 6.6 g ofN,N'-dicyclohexylcarbodiimide was added thereto, followed by stirring atroom temperature for 2.5 hours. 3.3 ml of benzyl alcohol was added tothe reaction solution, followed by stirring at the same temperature for2 days. Insoluble matters were filtered off, and then the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethylacetate=4/1+chloroform/methanol=50/1) to obtain 6.55 g of theabove-identified compound as a yellow solid.

(2) Preparation of 2-benzyl 3-tert-butyl(2RS,3RS)-5-oxotetrahydrofuran-2,3-dicarboxylate

6.53 g of(2RS,3SR)-2-benzyloxycarbonyl-5-oxotetrahydrofuran-3-carboxylic acid wasdissolved in 70 ml of chloroform, and 4.53 g of 4-dimethylaminopyridine,7.11 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideand 4.70 ml of tert-butyl alcohol were sequentially added thereto,followed by stirring at room temperature for 14 hours. The reactionsolution was poured into 1N hydrochloric acid cooled with ice andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, and the drying agent was filtered off. Then, thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=5/1),to obtain 5.16 g of the above-identified compound as a white solid.

(3) Preparation of(2RS,3RS)-3-tert-butoxycarbonyl-5-oxotetrahydrofuran-2-carboxylic acid

4.92 g of 2-benzyl 3-tert-butyl(2RS,3RS)-2-oxotetrahydrofuran-2,3-dicarboxylate was dissolved in 50 mlof ethyl acetate, and 500 mg of a 10% palladium-carbon catalyst wasadded thereto, followed by catalytic reduction at room temperature underhydrogen atmospheric pressure for 3 hours. The catalyst was filteredoff, and then, the filtrate was evaporated to dryness under reducedpressure to obtain 3.44 g of the above-identified compound as a whitesolid.

Reference Example 5 Preparation of 2,4-diisopropyl1-acetoxy-1,2,4-butanetricarboxylate (1) Preparation of diisopropyl4-hydroxy-4-phenyl-1,3-butanedicarboxylate

38 ml of a 1.5M lithium diisopropylamide cyclohexane solution wasdissolved in 400 ml of tetrahydrofuran, and 20 ml of a tetrahydrofuransolution containing 10.3 g of diisopropyl glutarate was dropwise addedat -78° C. in a nitrogen atmosphere. After stirring at the sametemperature for 30 minutes, 10 ml of a tetrahydrofuran solutioncontaining 3.9 g of benzaldehyde was dropwise added thereto, followed bystirring at -78° C. for 1.5 hours. 2N hydrochloric acid was added to thereaction solution, and the temperature was brought to room temperature.Then, the mixture was extracted with ethyl acetate. The organic layerwas washed with 1N hydrochloric acid, a saturated sodiumhydrogencarbonate aqueous solution and a saturated sodium chlorideaqueous solution and dried over anhydrous magnesium sulfate. The dryingagent was filtered off, and then, the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=5/1+3/1) to obtain 6.14 g of theabove-identified compound as a colorless oily substance.

(2) Preparation of diisopropyl4-acetoxy-4-phenyl-1,3-butanedicarboxylate

70 mg of dimethylaminopyridine was added to a mixed solution comprising6.13 g of diisopropyl 4-hydroxy-4-phenyl-1,3-butanedicarboxylate, 30 mlof pyridine and 6 ml of acetic anhydride, followed by stirring at roomtemperature for 1.5 hours. 2N hydrochloric acid was added to thereaction solution, and then the mixture was extracted with ethylacetate. The organic layer was sequentially washed with 2N hydrochloricacid, a saturated sodium hydrogencarbonate aqueous solution and asaturated sodium chloride aqueous solution and dried over anhydrousmagnesium sulfate. The drying agent was filtered off, and then, thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=5/1)to obtain 4.68 g of the above-identified compound as a colorless oilysubstance.

(3) Preparation of 2,4-diisopropyl 1-acetoxy-1,2,4-butanetricarboxylate

4.68 g of diisopropyl 4-acetoxy-4-phenyl-1,3-butanedicarboxylate wasdissolved in a mixed solution of 20 ml of carbon tetrachloride, 20 ml ofacetonitrile and 20 ml of water, and 9.7 g of disodium phosphate 12hydrate and 11.2 g of sodium periodate were added thereto. Then, 58 mgof ruthenium chloride was added thereto under cooling with ice, followedby stirring at room temperature for 3 days. Insoluble matters werefiltered and then washed with a saturated sodium hydrogencarbonateaqueous solution and chloroform. The filtrate and the washed solutionwere put together, and then the aqueous layer was separated. Theobtained aqueous layer was acidified with 6N hydrochloric acid and thenextracted with ethyl ether. The organic layer was washed with asaturated sodium thiosulfate aqueous solution and a saturated sodiumchloride aqueous solution and then dried over anhydrous magnesiumsulfate. The drying agent was filtered off, and then, the solvent wasdistilled off under reduced pressure to obtain 1.58 g of theabove-identified compound as a colorless oily substance.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have excellent inhibitoryactivities against protein-farnesyl transferase (PFT) and thus areuseful as antitumor agents.

We claim:
 1. A compound of the formula (I) or a pharmaceuticallyacceptable salt or ester thereof: ##STR99## wherein each of ##STR100##which are the same or different, is selected from the group consistingof phenyl, naphthyl and anthryl, and a heteroaromatic ring group whichis a 5- or 6-membered monocyclic ring which contains --O--, --S-- or--N--; A is a C₂₋₉ saturated or unsaturated aliphatic hydrocarbon groupwhich is unsubstituted or substituted by lower alkyl, hydroxyl, lowerhydroxyalkyl, lower alkoxy, carboxyl, lower carboxyalkyl, phenyl,naphthyl or anthryl or alkyl-substituted phenyl, naphthyl or anthryl;--X--Y-- is selected from the group consisting of --O--CHR^(a) -- andCHR^(a) --O, wherein R^(a) is hydrogen or lower alyl; each of R¹, R²,R³, R⁸ and R⁹ which are the same or different, is hydrogen, halogen,hydroxyl, lower alkyl or lower alkoxy; each of R⁴ and R⁵, which are thesame or different is hydrogen, halogen, hydroxyl, amino, nitro, cyano,carboxyl, lower alkoxycarbonyl, carbomoyl, lower alkyl carbomoyl, loweralkyl, lower hydroxyalkyl, lower fluoroalkyl or lower alkoxy; R⁶ islower alkyl; and R⁷ is hydrogen or lower alkyl.
 2. The compound of claim1, wherein A is a group of the formula. ##STR101## wherein R¹⁰ ishydrogen, hydroxyl, lower hydroxyalkyl, lower alkoxy or carboxyl; R¹¹ ishydrogen, hydroxyl, lower alkoxy, carboxyl or lower carboxyalkyl; R¹² ishydrogen, lower hydroxyalkyl or carboxyl; R¹³ is hydrogen, hydroxyl orcarboxyl; and each of m and n which are the same or different is aninteger of from 0 to
 2. 3. The compound of claim 1, wherein A is a groupof the formula: ##STR102## wherein R¹² is hydrogen, lower hydroxyalkylor carboxyl; R¹³ is hydrogen, hydroxyl or carboxyl; p is 0 or 1, andeach of q and r which are the same or different, is an integer of from0to2.
 4. The compound of claim 1, wherein ##STR103## which are the sameor different, is selected from the group consisting of phenyl, naphthyland anthryl.
 5. The compound of claim 1, wherein each of ##STR104##which are the same or different, is selected from the group consistingof phenyl, naphthyl and anthryl; and ##STR105## and is a heteroaromaticring group which is a 5- or 6-membered monocyclic ring which contains--O--, --S-- or --N--.
 6. The compound of claim 1, wherein each of##STR106## Ar is a heteroaromatic ring group which is a 5- or 6-memberedmonocyclic ring which contains --O--, --S-- or --N--; and each of##STR107## which are the same or different, is selected from the groupconsisting of phenyl, naphthyl and anthryl.
 7. The compound of claim 1,wherein ##STR108## which are the same or different, is a heteroaromaticring group which is a 5- or 6-membered monocyclic ring which contains--O--, --S-- or --N--; and each of ##STR109## which are the same ordifferent, is selected from the group consisting of phenyl, naphthyl andanthryl.
 8. The compound of claim 1, wherein said heteroaromatic ringgroup which is a 5- or 6-membered monocyclic ring which contains --O--,--S-- or --N-- is selected from the group consisting of pyrrolyl,imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,oxazolyl, isoxazolyl, furyl, thenyl, thiazolyl and isothiazolyl.
 9. Thecompound of claim 8, wherein said heteroaromatic ring group which is a5- or 6-membered monocyclic ring which contains --O--, --S-- or --N-- isselected from the group consisting of furyl, thienyl, pyridyl,pyrimidinyl. oxazolyl, isoxazolyl and thiazolyl.
 10. The compound ofclaim 1, wherein each of R² and R¹ -R⁹ is lower alkyl and each isselected for the group consisting of methyl ethyl.
 11. The compound ofclaim 1, wherein lower hydroxyalkyl for either R⁴ or R⁵ is hydroxymethylor hydroxyethyl.
 12. The compound of claim 1, wherein each of R¹ -R⁵, R⁸and R⁹ is lower alkoxy and each is selected from the group consisting ofmethoxy, ethoxy and methylenedioxy.
 13. The compound of claim 1, whereinlower fluoroalkyl for either R⁴ or R⁵ is fluoromethyl, difluoromethyl,trifluoromethyl, 1 -fluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl orpentafluoroethyl.
 14. An anti-tumor agent, which comprises a compound ofclaim 1, or a pharmaceutically acceptable salt or ester thereof, and apharmaceutically acceptable excipient.